DE2362589A1 - Antiphlogistic phenyl-alkyl or alkenyl ketones or carbinols - have superior activity to phenylbutazone and are used in arthritis and rheumatism treatment - Google Patents

Abstract

Cpds. of formula (I) where R1 = isobutyl. phenyl (opt. substd. in posn. 2 by Cl or F) opt. methylated cyclohexyl, cyclopentyl or cycloheptyl; R2 = H, F, Cl or Br; R3 = methyl or ethyl or when R1 = opt. substd. phenyl or when R1 = cyclohexyl and R2 = halo then R3 may also be H; Z1,Z2 = H or together form a second bond; A = m = 2,4,6,8 or 0 when R1 is not = unsubstd. phenyl and/or R2 = halo and/or R3 = methyl or ethyl and/or A = CHOH are antiphlogistics used in the treatment of rheumatic arthritis, osteoarthritis, articular rheumatism and to relieve pain due to rheumatism and other inflammatory states. The cpds. are active orally and in pharmacological tests show superior activity to that phenylbutazone.

Description

Case 5/615
Dr Bu./Zo.

DR. KARL THOMAE GMBH., BIBERACH AN DER RISS

New Araliphatic Ketones and Carbinols and Processes for their manufacture

The invention relates to new araliphatic ketones and carbinols of the general formula I,

C-CH (-CHp) -AC-CH ₉ V-CH,

j and process for their preparation.

The compounds of the general formula I have pharmacologically valuable properties, they have an anti-inflammatory effect in particular.
In the above general formula I mean the radicals

R ₁ and Rp are hydrogen atoms or one of these two radicals: fluorine or chlorine atom and. the other a hydrogen- '-. atom;

R is a hydrogen atom, the methyl or ethyl group; s H. ■

, A is the group ^ C = O or ^ C

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Ζ. and Zp hydrogen atoms or, if m is zero adopts, together, an additional carbon-carbon bond;

the symbol η means the numbers 0, 1, 2, the symbol m the numbers 2, 4, 6, 8, or zero, provided at least one of the following four Requirements is met: R. or Rp is a fluorine or Chlorine atom or R is the methyl or ethyl group or η is the number 1 or 2 or A is the group \. —H

* 0H

The compounds of general formula I can be broken down into the following Manufacturing process:

1. All of the compounds of the general formula I can be obtained by reacting organometallic compounds with compounds containing suitable polar CX multiple bonds (the meaning of X is defined below) and then by subsequent hydrolysis
a) by reaction of metal organyls of the general formula

M (-CH ₂ ) _n -CH ₃ II

with compounds of the general formula III,

«X

I H

C-CH (-CH-) - C-Y III

II ² ' ₁ z ₂

or
b) by reaction of metal organyls of the general formula IV,

5 0 9828/1037

C - CH (-CH ₂ ) -K ^Z 1 ^Z 2

with compounds of the general formula V

X
YC (-CH ₂ ) _n -CH ₃ (V)

In the general formulas II _s III, IV and V, the symbols R, R ^ ₅ Rp, Z ^, Zp, m and η the initially defined, X is an oxygen atom, if Y is a hydrogen atom or an _NH? = Group, or a nitrogen atom, if Y takes on the meaning of an additional bond between C and X, M a lithium atom or the residue MgHaI, in which Hai is a chlorine, bromine or death atom.

If the radical -CY in compounds of the general formulas III and V is the group -C-NH ₂ or the cyano group

after reaction with the organometallic compounds of the general formulas II or IV and subsequent hydrolytic work-up, biphenyl derivatives of the general formula I in which A is the keto group are obtained.

If, on the other hand, the radical -C-Y in compounds of the general formulas III and V means a group -CH =O, then one obtains as End products Compounds of general formula I in which

H
A is the group ^ C is ₉ if you have the metal organyl in

OH

Excess or in at least a stoichiometric proportion lets act; if, on the other hand, the aldehydes corresponding to the general formulas III and V are used for these

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This conversion in excess, follows the actual conversion of the organometallic compound with the carbony compound another oxidation catalyzed by the metal alcoholates formed by the excess aldehyde so that, after hydrolysis, mixtures of ketones and alcohols of the general formula I are obtained, ie in which A is the group

,, C = O or ^, C means. Let out of these mixtures

OH

then go through the steps under 3. and k. Reduction or oxidation processes described produce uniform end products of the general formula I _s in which A is either the group ^ CHOH or ^ C = O.

The reactions of the metal organyls of the general formulas II and IV with the compounds of the general formulas III and V is carried out at temperatures between -80 ° C and + 1 ^ ⁰ ° C, preferably -4o ⁰ C to +60 ⁰ C, preferably in Gepenwart of ethereal solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, anisole, optionally mixed with aromatic hydrocarbons such as benzene or toluene. The reaction can occasionally, but also with advantage, be carried out in aliphatic hydrocarbons such as n-entane, n-hexane or n-heptane. Carboxamides corresponding to the general formulas III and V are advantageously reacted in the presence of methylene chloride, preferably at temperatures between 30.degree. And 50.degree.

Compounds of the general formula I, in which Z .. and Z "together represent an additional CC bond, can easily be _{hydrogenated to the saturated compounds of the general formula I, in which Z. and Z" represent 2} hydrogen atoms
a) by catalytic hydrogenation

The catalytic hydrogenation takes place in contrast to the usual Catalysts, especially in the presence of finely divided metals of the VIII, Meben group of the periodic

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Systems, for example from Raney cobalt, Raney nickel, palladium on charcoal, palladium on barium sulfate, platinum or platinum (IV) oxide. The hydrogenation is broken down after 1 to 1.2 mol of hydrogen have been absorbed. Solvents are carbinols such as methanol, ethanol, isopropanol or aromatic hydrocarbons such as benzene, or ethers such as dioxane or esters of lower aliphatic carboxylic acids, for example methyl acetate or ethyl acetate, or mixtures of the above Solvent used. One works at temperatures between 0 and 40 ⁰ C, preferably at room temperature, and a pressure of 0 to 100 at, preferably 1 to 5 at.

Assuming compounds of the general formula I from _s in which Z. and Z ₂ together denote an additional CC bond and A is the group C = O, the carbony1 group is generally also partially reduced. The resulting mixtures of the general formula I corresponding ketones and carbinols in which Z and Zp are hydrogen atoms, may be prepared by reduction or oxidation, as described in 3. and ¹ J., light in uniform end products of the general formula I, in the A either the group ^. C = O or the group ^ CC ^ q _H , transfer or separate well from one another by column chromatographic methods.

The partial reduction of the carbon group A does not occur, however, when the colloidal nickel boride obtained from nickel (II) acetate by reduction with sodium borohydride in ethanol (P-2 catalyst) used as a hydrogenation catalyst.

b) The saturation of the olefinic double bond in starting compounds of the general formula I, in which Z ₁ and Z _{5 represent} an additional bond and A represents the group ^ C = O, can also be carried out with nascent hydrogen. Reduction with sodium amalgam in an acidic medium is suitable ^; by carefully adding dropwise diluted vinegar

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acid alkaline reaction must avoid, as well as the action " of zinc amalgam, preferably in mixtures of ethanol and aqueous acetic acid and at temperatures from 60 ° C to Boiling point of the solvent mixture works.

Is suitable for saturating the olefinic double bond furthermore the electrolytic reduction in a nearly neutral or in an acidic medium. For example, the relevant o £, ß-unsaturated Ketone reduced in acetic acid in the presence of dilute sulfuric acid in the cathode compartment of an electrolysis cell, whereby the aioden space with 20 percent. Sulfuric acid filled will. Lead cylinders or a layer of mercury about 1 cm high are used as cathodes, lead or carbon rods as anodes Consideration. However, electrolysis can also be carried out using a mixture of ethyl acetate, ethanol, water and potassium acetate be carried out as catholyte.

Finally, compounds of the general formula I,

in the Z. and Z _? Hydrogen atoms and A is the group -C = O

means, also obtained by the fact that the corresponding ofc, ß-unsaturated ketones of the general formula I in one aqueous-ethanolic ammonia solution with aqueous titanium (III) chloride warmed up on the steam bath.

3. Compounds of the general formula I in which A is the group

C = O, or the mixtures obtained by process 1 which contain such compounds can easily be reduced to compounds of the general formula I in which A is the group ^ CC ^ ₀ H ^:

a) by reduction using complex hydrides:

Possible complex hydrides are: alkali or alkaline earth aluminum hydrides, for example lithium aluminum hydride, sodium aluminum hydride, magnesium aluminum hydride, alkoxy aluminum hydride, for example sodium bis (2-methoxy-ethoxy) -

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dihydroaluminat, lithium trimethoxyaluminiumhydridc, lithium tris (tert "-butoxy) aluminum hydride _s alkali and Erdalkaliborhydride and -alkoxyborhydride, for example, lithium borohydride, sodium borohydride, calcium borohydride _s lithium cyanoborohydride, sodium cyanoborohydride, Natriummethoxyborhydrid., zinc borohydride. Also, combinations of lithium aluminum hydride or sodium borohydride with Lewis acids, be'son- '■ DERS be used with aluminum chloride or boron trifluoride. ₃ Finally - if in the starting compounds the; general formula IZ ₁ and Zp hydrogen atoms are also diborane suitable for the reduction »Diborane does not need to be used as such j it can also be used in the solution in which the reduction is carried out _? be developed in situ. for example by reacting sodium borohydride in diethylene glycol dimethyl ether with anhydrous hydrogen chloride, with sulfuric acid _s chlorosulfonic acid, methanesulfonic acid, phosphoric acid, boron halides, tin (II) chloride, mercury (I) chloride, _s aluminum chloride or the like.

The reduction is carried out in a suitable solvent, preferably in ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane _9, diethylene glycol dimethyl ether, tri: ethylene glycol dimethyl ether, occasionally also in aromatic. Hydrocarbons, for example in benzene, or in mixtures of these solvents. Reductions with sodium borohydride, sodium cyanoborohydride and sodium trimethoxyborohydride can be used; can also be carried out in lower alcohols, preferably in ethanol, or in alcohol-water mixtures. Suitable Re-; Production temperatures are - depending on the ί complex hydride used - between -80 and + 10O ⁰ C. Temperatures between 0 and +30 ⁰ C. are preferred.

In general, these reductions with complex ■

Metal hydrides the geometric arrangement of the substituents;

on a possibly existing olefinic double bond \

unchanged _s occasionally, however, partial isomeric j

screening _s observed so that i after workup mixtures

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isolated from E and Z isomers.

b) with primary or secondary alcohols in the presence of alcoholates of metals of the 1st to 3rd main group of the periodic system, for example with isopropanol in the presence of aluminum isopropylate _s Magnesiumisopropylat, sodium ethylate, Aluminiumdichlorisopropylat. It is preferred to work in aromatic hydrocarbons as solvents, for example in benzene or toluene solution, and at elevated temperatures, preferably at the boiling point of the solvent used, the ketone formed, for example acetone, expediently being continuously distilled off from the reaction mixture. However, the reduction can also be carried out in the absence of the primary or secondary alcohols with the metal alcoholates alone, for example with molten aluminum isopropoxide or with aluminum isopropoxide in toluene solution.

c) by the action of base metals in an alkaline environment: Sodium, sodium amalgam, calcium, for example, are suitable Magnesium, zinc, zinc amalgam, aluminum or aluminum amalgam. Lower alcohols such as methanol are used as solvents or ethanol, wet ether, or wet benzene. You work at temperatures between room temperature and the boiling point of the solvent used. In a variant of this process, sodium is used to reduce in liquid ammonia and in the presence of excess ammonium chloride.

If in compounds of the general formula IR ₁ or R _{2 have} the meaning of a chlorine atom, then in all reductions with base metals it is to be expected that the chlorine atom will be partially or fully replaced by hydrogen. Any olefinic double bonds that may be present are also saturated, so that in the end products of the general formula I Z. and Z "obtained can only have the meaning of a hydrogen atom.

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d) by catalytic hydrogenation:

A whole range of catalysts can be used for this reduction: platinum from hexachloroplatinic acid, from ammonium hexachloroplatinate ₉ . Platinum (IV) oxide _s Raney nickel, palladium on TIeTkOhIe ₄ copper-barium-chromium oxide, ruthenium or rhodium on animal charcoal, copper chromite. One works under alkaline, neutral or acidic conditions in solvents such as alcohols, mixtures of water and alcohols, ethers, for example dioxane, in ethyl acetate or lower aliphatic carboxylic acids, for example glacial acetic acid or trifluoroacetic acid. The metal catalysts mentioned are used at temperatures between 20 and 10O ⁰ C, but preferably above +40 ⁰ C; the oxide catalysts require temperatures between 100 and 250 ° C.

In the case of carbony compounds of the general formula I in which Z. and Z "together mean an additional C-C bond, the saturated ketone is formed first, which is only subsequently converted into a secondary by a second mole of hydrogen Alcohol is reduced.

e) by reduction using thiourea S.S-dioxide:

The reaction is carried out in the presence of an aqueous-ethanolic solution carried out by caustic alkalis, preferably at the boiling point of the solvent mixture used. Used appropriately an excess of said reducing agent, up to 3.0 moles per mole of the substrate to be reduced. It It has proven useful to use 2 moles of alkali metal hydroxide per mole of reducing agent.

Compounds of the general formula I in which A is the group

^ CC ^ "7" means, or the mixtures obtained by method 1, which contain such compounds can easily be oxidized to compounds of the general formula I in which A the group ^, C = O means.

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The oxidation takes place

a) with Cr (VI) compounds:

Particularly noteworthy as suitable Cr (VI) compounds are: sodium and potassium dichromate, chromium (VI) oxide and di-tert. butyl chromate. You can work in a number of solvents, for example in water, glacial acetic acid, acetone, petroleum ether, benzene, carbon tetrachloride, pyridine or dimethylformamide or in mixtures thereof. Is carried out at 0-100 ⁰ C, preferably at room temperature or moderately elevated temperatures.

Special mention should be made of oxidations with

Chromium (VI) oxide or dichromate in an aqueous sulfuric acid solution, where it is expedient to use glacial acetic acid, possibly also benzene, as an additional solvent;

Chromium (VI) oxide or dichromate in glacial acetic acid; Chromium (VI) oxide in pyridine;

Chromium (VI) oxide in aqueous sulfuric acid solution in the presence of acetone;

Di-tert-butyl-chromate in non-polar solvents such as Petroleum ether, carbon tetrachloride, or benzene;

Chromium (VI) oxide in dimethylformamide in the presence of concentrated Sulfuric acid.

b) with manganese (IV) oxide:

This process is especially suitable for the oxidation of oG, ß-unsaturated carbinols of the general formula I, in which Z ₁ and Z ₂ thus represent an additional CC bond.

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Expedient to use a large excess of oxidizing agent ο Suitable solvents preferably acetone petroleum ether _s ,, Diäthylather and tetrahydrofuran into consideration. Also useful is the use of benzene ₉ chloroform or tetrachloromethane as solvent "The reaction is preferably carried out at temperatures between 0 ° and 100 ⁰ C ₉ but _s carried out in the oxidation of the general formula I corresponding © & _ß ~ unsaturated carbinols at room temperature ( Z ₁ and Zp together form an additional CC bond) even at the boiling point of the solvent used.

c) with ketones in the presence of alcoholates of metals

1. to 3 »main group of the periodic table. To aluminum alkoxides as catalysts have proven to be oxidized carbinol, aluminum phenoxide _s Al _s uminiumisopropylat but especially aluminum _s-butoxide as hydrogen acceptors acetone, 1,4-benzoquinone and cyclohexanone, advantageously using benzene or toluene as additional solvents. It is preferred to work at elevated temperatures up to the boiling point of the solvent mixture used and with a large excess of the hydrogen acceptor.

d) with anhydrous dimethyl sulfoxide in the presence of N.N'- ^ dicyclohexylcarbodiimide and acidic agents. In particular, medium-strength inorganic or organic acids come into consideration as acidic agents: For example, anhydrous phosphoric acid, phosphorous acid, cyanoacetic acid or pyridinium phosphate, pyridinium sulfate; Dichloroacetic acid and pyridinium trifluoroacetate have proven particularly useful. The acidic agents are preferably used in an amount of 0 _s 5 moles per mole oxidized carbinol of the general formula I; However, it can also be used _a smaller or larger quantities, for example, 0 _s l or 1.0 molar equivalents of acid agent. Dicyclohexylcarbodiimide is generally used in an excess of at least 2 moles per mole of carbinol, preferably in an amount of 3 moles per mole of carbodiimide; excess dicyclohexylcarbodiimide is used

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after the end of the oxidation preferably removed by adding oxalic acid, which reacts rapidly with dicyclohexylearbodiimide to form carbon dioxide, carbon monoxide and Ν, Ν ¹ -dicyclohexylurea. Due to its minimal solubility in most organic solvents, the dicyclohexyl urea can easily be separated from the desired product. The amount of dimethyl sulfoxide used for oxidation is not critical; there are .jedoch at least xven equimolar amounts - based on the carbinol to be oxidized required.

It is often advantageous to use inert cosolvents in the reaction mixture to be added, especially those which are immiscible with water, for example benzene or allyl acetate. Through this the limited solubility of dicyclohexylcarbodiimide in dimethyl sulfoxide is improved, and the reaction proceeds less exothermic, as the solution is less concentrated.

Instead of N, N ¹ -dicyclohexylcarbodiimide, other substituted carbodiimides can also be used, for example Μ, Ν'-diisopropylcarbodiimide, Ν, Ν'-diethylcarbodiimide, N, M ^f -di (p-tolyl) -carbodiimide, N -Cyclohexyl-N '- / l- (3-pyridyl) -l-ethy37carbodiimide or N-cyclohexyl-N'-Cp-toluenesulfonyD-carbodiimide, without these dehydrating and dimethyl sulfoxide activating carbodiimides in these oxidation reactions against N, M'-car dicyclohexyl but bring significant advantages. Some other compounds, which are similar in mechanistic behavior to the carbodiimides and also catalyze oxidations by dimethyl sulfoxide, are also suitable, for example N-ethyl-5-phenyl-isoxazolium-3'-sulfonate, trichloroacetonitrile, xthoxyacetylene or diphenylketene-p-tolylimine . Oxidations with dimethyl sulfoxide in the presence of inorganic or organic acid anhydrides, for example acetic anhydride, benzoic anhydride, phosphorus pentoxide, polyphosphoric acid or pyridine anhydrosulfuric acid, can also be carried out.

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Instead of dimethyl sulfoxide, other sulfoxides can also be used find, for example, tetramethylene sulfoxide.

e) with 2.3-dichloro-5.6-dicyan-1. ⁱ -benzoquinone in inert solvents such as dioxane, anisole, benzene or toluene or mixtures thereof and at temperatures between 10 ° C and the boiling point of the solvent in question "

5. Compounds of the general formula I ₅ in which A denotes the group can also be obtained by saponification and subsequent decarboxylation of β-keto esters of the general formulas vi and VII,

Il

- c ™ ~ (caj -CH, vi

COOR ₅

- CH- CHo-

COOR ₅

Z ₁ , Z "and η the initially de

in which the symbols R, FL, R

Have defined meanings, m can assume the values 2, 4, 6, 8 and Rj- an alkyl, cycloalkyl, aryl or aral can mean kylrest produce.

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The saponification is carried out in an alkaline, usually in a weakly alkaline, or in an acidic solution. Decarboxylation is effected by acids and bases, especially weak ones
Bases such as aniline or pyridine, catalytically accelerated. ^;

Particularly easy compounds of the general formatting may '■ my VI and VII are hydrolyzed in which R ₁ - tertiary

Means alkyl radical. In a variant of this process;

the such tert. Alkyl ester pyrolyzed, preferably in counter!

was a trace of p-toluenesulfonic acid, where ^ next to the searched ^! Compounds of the general formula I in which A is the group

> C = 0, yet carbon dioxide and a Isoalkylen advertising formed \

the. ;

The alkaline cleavage of the ß-keto esters of the general formulas _: VI and VII is preferred in aqueous alkali or alkaline earth ■ hydroxide solutions, for example in 5% aqueous sodium hydroxide solution,
carried out. Water-miscible cosolvents, such as ethanol,
n-propanol or dioxane can be added. One works _; initially at room temperature, but then boils under reflux for a few hours to complete the elimination of carbon dioxide. ■

Aqueous mineral acids, for example sulfuric acid, phosphoric acid and mixtures of glacial acetic acid, are preferably suitable for acidic hydrolysis and aqueous sulfuric acid, acidic ion exchangers such as; Dowex 50 W χ 2.

In a variant of this process, esters of the general
Formulas VI and VII by heating with sodium chloride in the presence of moist dimethyl sulfoxide to temperatures between
140 and 185 ⁰ C in the A decarbalkoxylated to obtain in one step directly and in good yields ketones of the general formula I, the group ^ C = O. Instead of sodium chloride, other alkali metal halides and pseudohalides,
for example alkali metal fluorides, chlorides, bromides, sodium cyanide or sodium azide, as well as sodium phosphate can be used.

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Dimethyl sulfoxide can be replaced by other dipolar aprotic solvents, for example dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; in the lower boiling solvents _s as in moist dimethylformamide,; however, longer reaction times are required.

Compounds of the general formula I ₃₁ in which R is a hydrogen

atom ", Z. and Z" together form a CC bond, A is the group ^ C = O; mean and m takes the value zero ₃ is also obtained! a) by condensation of aldehydes of the general formula VIII,

VIII

R ₁

in which the leftovers

Have the meanings mentioned above, R ₁ and Rp _s with ketones of the general formula IX ₉

H ₃ CC (-CH ₂ ) _n -CH ₃ (IX) in which η can assume the values mentioned at the beginning o

The reaction is catalyzed by bases. Suitable basic catalysts are alcoholic or aqueous solutions of alkali metal or alkaline earth metal hydroxides _s particular aqueous Natronoder potassium hydroxide, aluminum alkoxides, piperidine or basic ion exchangers _β In order to avoid VIII a reaction of the ketone of the general formula IX with 2 molecules of the aldehyde of the general formula ^ is the ketone suitably used in a 3- to 100-fold molar excess "As additional solvents of water and lower alcohols having 1 to 3 carbon atoms or mixtures thereof be added = The reaction lord at -10 ^ 50 ⁰ Cj preferably at 20 to 25 ⁰ C. carried out ο

5 0 9828/1037

In a variant of this process is carried out using zinc oxide as catalyst and at temperatures between 150 and 200 ⁰ C ₃ preferably 170 to 19O ⁰ C _5, and under elevated pressure of 10 atmospheres to 300, preferably 50 at, using inert shielding gases, distortion as of nitrogen.

In all these processes, if the reaction is carried out appropriately, practically only the methyl group adjacent to the carbonyl group is attacked, but not the methylene group, so that the above-formulated compounds of general formula I with the meanings of the radicals P, Z ₁ , Zp and A mentioned above are formed almost exclusively. With regard to the olefinic double bond, the aryl and acyl radicals in these compounds have the E configuration. ^Ci

If η has the value zero in a ketone of the general formula IX, If an aldehyde of the general formula VIII is condensed with acetone, acidic agents, in particular mineral acids, can be used as catalysts for the condensation reaction. Hydrogen chloride has proven particularly useful for this purpose and hydrogen bromide and their aqueous or alcoholic solutions.

b) by reacting aldehydes of the general formula VIII with triphenylphosphine acylmethylenes of the general formula X,

p = CH - c - (cH ₂ ) _n -ca χ

in the

η can assume the values mentioned at the beginning. The reaction is preferred in ethereal solvents, e.g. in tetrahydrofuran, Ethylene glycol dimethyl ether, dietylene pilycol dimethyl

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ether _s and at temperatures between 50 and 120 ⁰ C ₃ , preferably 60 to 80 ° C _s carried out.

7. Compounds of the general formula I ₅ , in which Z. and Z "together represent a CC bond and A the group ^ C = O, m assumes the value zero and the other radicals have the meanings defined at the beginning," can prepare as follows: by condensation of aldehydes of the general formula VIII or of ketones of the general formula XI ₅

R ₂

■ in the

R is a methyl or ethyl group _s with crotons ^ 'ureesters of the general formula XII,

XII

H ₃ C ^C0 2 ^R 4

in which the leftovers

R, and R || may be the same or different from one another and lower alkyl radicals with 1 to 1 carbon atoms, cycloalkyl radicals with 5 to 7 carbon atoms, aryl or aralkyl radicals with a maximum of 10 carbon atoms, the condensation under anhydrous conditions and in the presence of strong bases, for example alkali metal alcoholates, are preferred Potassium methylate or potassium tert-butylate, in the presence of

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dipolar aprotic solvents such as hexamethylphosphoric triamide or dimethylformamide, or in the presence of Al-

Potash metal amides, for example lithium amide, preferably takes place in liquid ammonia,

and subsequent saponification and decarboxylation of the primary intermediate products of the general formula XIII,

R OR ₃

C = CH -C = CH-COOH XIII

κ ^w

in which the radicals R, R ^, R "and R, the meaning given above correspond. &

In a preferred embodiment of the method of the intermediates of general formula XIII konzertrierte hydrochloric acid is not isolated, but upon completion of the condensation reaction to the reaction mixture and process by brief heating at 80 to 100 ⁰ C directly and in good yield in one-op f the desired End product obtained.

8. Compounds of the general formula I in which Z. and Zp are hydrogen atoms and A mean the group ^ C = O, he too hold by thermal decarboxylation of a mixture of carboxylic acids of the general formulas XIV and XV,

H-CH ₂ - (CH ₂ ) _m -C0 ₂ H

XIV

H0 ₂ C-

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in which the symbols R ₅ R ^ ₈ R ₃₅ m and η have the meanings given at the beginning »Suitable, for example, is the dry distillation of a mixture of the calcium or barium salts of acids of the general formulas XIV and XV, as well as a contact process in which a mixture of acids of the general formulas XIV and XV at temperatures between 300 and 480 ⁰ C over catalysts of calcium, barium or thorium oxide or manganese (II) oxide is passed on to pumice stone and thereby directly into a ketone of the general formula I ₉ in the Z ₁ and Z _{n are} hydrogen atoms and A is the group 'S »^

^ CQ means _s and breaks down into carbon dioxide and water.

In a further variant, carboxylic acids of the general formula XIV are mixed with alkali metal salts of carboxylic acids of the general formula Formula XV and the anhydrides of acids of the general formula XV are pyrolyzed.

In all these process variants arise Ketongemische, from which the desired compounds of general formula I, in which A represents the group ^ .C = O, _{s s} fractional crystallization or chromatographic methods can be easily obtained pure by standard physical separation methods, for example fractional distillation. The yields of the desired reaction products are particularly good when the carboxylic acids of the general formula XV are used in excess.

The organometallic compounds used as starting compounds general formula. 11 and the compounds of general Formulas V and IX are known from the literature.

Compounds of the general formula III in which Y is a hydrogen atom are obtained in ways known per se, for example by reducing a corresponding nitrile. The nitrile is, for example, with the equivalent amount of a complex hydride such as lithium aluminum tri-tert.butoxyhydrid Lithiumtriäthoxyaluminiumhydrid or in solvents such as tetrahydrofuran at temperatures between -70 and ⁰ * 20 ° C

SO 9 8 2 B / 1037

reduced; the aldehyde is released by hydrolysis with water or dilute acids (cf. H.C. Brown et al., Tetrah. Letters 3, 9 (1959).

The compounds of the general formula III, in which X is an oxygen atom, Y is the NHo group and Z and Z are ₂ hydrogen atoms, can be derived from biphenyl compounds of the general formula XVI, if m is equal to zero,

- \ / - ^c - ^¥

IF-J.

in the W ^R 2 ^R 1 ^

the hydroxy group, a halogen atom or any acyloxy radical means by reaction with 1,1-dichlorotethylene in sulfuric acid produce, wherein the intermediate product that forms is then hydrolyzed by adding water. The one with it The carboxylic acid obtained is then converted into acid chloride and this is converted into the corresponding acid amide of the general type by means of ammonia Formula III converted.

Compounds of the general formula III in which X is an oxygen atom, Y is the NHp group and Z. and Z ₂ together are a double bond, are obtained as follows: Reaction of a ketone of the general formula XI,.

XI

with the zinc compound of an oC-halocarboxylic acid ester leads to an ester of the general formula XVIII,

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C-CH ₂ - COOR ₆ XVIII

OH

in which the rest

^: Rg represents an alkyl radical. This reaction is effected in an organic solvent _s a, for example, in ether or in benzene or toluene at temperatures between 20 and 60 ° C. The ester of the general formula XVIII is then treated with a dehydrating agent, preferably in an inert solvent which is immiscible with water, advantageously using a water separator, at temperatures up to the boiling point of the reaction mixture. Suitable dehydrating agents are, for example, salts of pyridine or of alkyl pyridines with ecclogic acids, potassium hydrogen sulfate, zinc chloride, phosphorus oxyhalides or p-toluenesulfonic acid, sulfuric acid or phosphoric acid, and solvents such as benzene, toluene or xylene. The resulting unsaturated ester is then converted by means of ammonia into the compound of the general formula III, in which Y is the NHp group, X is an oxygen atom and Z ₁ and Z together are a double bond. The nitriles falling under the general formula III can be produced therefrom by dehydration.

Compounds of the general formula III, in which X is a nitrogen atom and Y is an additional bond between the carbon atom and X, Z. and Z "are hydrogen atoms and the radicals R, R. and Rp are as defined above, that is, the nitriles falling under the general formula III, • are also accessible, for example, as follows: a compound of the general formula XIX,

I.

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CH - CH ₂ - Hal XIX

in the

Hal denotes a halogen atom, preferably a bromine atom , is reacted with potassium cyanide to form a corresponding nitrile of the general formula III, in which m is equal to zero and Z ₁ and Z ₂ denote hydrogen atoms. If desired, these nitriles can be saponified to give the corresponding carboxylic acids, which are then reduced with lithium aluminum hydride in ether to give the corresponding alcohols; these alcohols are then converted by means of phosphorus (III) halides to the corresponding compounds of the general formula XIXa, which differs from the general formula XIX in that the side chain is around a -CH _? -Group is extended. From the compound of the general formula XIXa, the nitrile, which has been lengthened by a further -C ^ group in its side chain, can then be prepared in the same way by means of potassium cyanide. By repeating these steps several times if necessary, all of the nitriles with m ^ O corresponding to the general formula III are accessible.

These nitriles in turn can also be used as starting compounds saponify carboxylic acids of the general formula XIV used for process 8.

The compounds of the general formula XIX can be prepared, for example, as follows: by reacting an appropriately substituted one Biphenyls with ethoxalyl chloride and anhydrous aluminum chloride give the corresponding 2- (4-biphenylyl) glyoxylic acid ester, which is saponified and, after reaction with one mole of an alkyl magnesium bromide, a corresponding 2- (4-biphenylyl) -2-hydroxyalkanoic acid results. Using hydriodic acid in

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2352583

Acetic acid can be used to obtain the corresponding 2- ( ⁱ J-biphenylyl) alkanoic acid; the reduction of this acid with lithium aluminum hydride in ether leads to a 2- (M-biphenylyl) carbinol of the general formula XX,

CH - CH ₂ - OH XX

j which by heating with a phosphorus trihalide, e.g. with

j phosphorus tribromide, into the corresponding compound of the general

n formula XIX is transferable. ^Ä

j The metal organyls of the general formula IV can be found in

■ in a known manner from the corresponding halogen compounds

of the general formula XXI

CH - (CHp) - CHp Hal XXI -1 ^ά

^Z 1 ^Z 2

produce, in which the symbols, R, R ₁ , R ₂ , Z ^, Z ₂ and m are as defined, and Hal means a halogen atom.

Compounds of general formula XXI, in which Z. and Z are ₂ hydrogen atoms, are accessible via the compounds of general formula XIX in the manner described above by means of chain extension by reaction with potassium cyanide, saponification of the nitrile, reduction of the resulting carboxylic acid to Carbinol and conversion of the latter using phosphorus trihalides.

B09828 / 1037

Compounds of the formula XXI, in which Z. and Z- have an additional Forming a C-C bond is obtained, for example, by heating compounds of the general formula XXII,

Shark

XXII shark

in which Hai means a chlorine or bromine atom, with strong alkalis, for example with alcoholic potassium hydroxide solution to 120 ^° C. The compounds of the general formula XXII are obtained, for example, by reacting aldehydes of the general formula XXIII,

O XXIII

with phosphorus (V) halides. The compounds of the general formula XXIII are obtained, for example, from glycidic esters of the general formula Formula XXIV,

- COOR ₇ XXIV

in which the radical R "can mean an alkyl radical, by saponification with hot aqueous-alcoholic sodium hydroxide solution and subsequent decarboxylation of the aiycidic acids obtained after acidification. Let the compounds of general formula XXIV in turn by processes known from the literature from ketones of the general formula XI or aldehydes of the general formula VIII win by the action of a chloroacetic acid ester and sodium amide.

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The starting compounds of the general formula VI, in which Z ^ and Z _{2 represent} hydrogen atoms, can be prepared in that a compound of the general formula XXV,

XXV

in which R, R. and R _{2 are} as defined at the outset and Hal denotes a halogen atom, preferably a chlorine, bromine or iodine atom, with an alkali metal salt or alkoxymagnesium salt of a compound of the general formula XXVI,

R ₅ OOC - CH ₂ - C (-CHg) _n - CH ₃ XXVI

is implemented in the Rj- as defined at the beginning. As an alkali salt of the compound of the general formula XXVI, in particular the sodium or potassium salt is used as the alkoxymagnesium salt for example the ethoxymagnesium salt. The implementation of a halide of the formula XCV with a salt of the compound of the formula XXVI takes place, for example, in a lower alcohol. Leave it also advantageously carbonic acid esters, for example diethyl carbonate, use as a solvent to avoid alcoholysis. The reaction takes place at temperatures up to the boiling point the solvent used.

The starting compounds of the general formula VII can be prepared in the same way by reacting a compound of the general formula XIXa or an analogous compound of the general formula XIXa, whose side chain is extended by 2, Ί or 6 -CH ₂ groups, with an alkali metal salt or alkoxymagnesium salt Prepare compound of general formula XXVI.

The aldehydes of the general formula VIII are obtained, for example, from nitriles of the general formula XXVII,

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CN XXVII

R ₂

by reduction with NatTiumhypophospb.it in Re ^ enwart of Raney nickel in a solvent mixture of water, glacial acetic acid and pyridine according to the method of OG Backeberg and B. Staskun, J. Chem. Soc. (London) 1962 , 3961.

Aldehydes of the general formula VIII, in which R. is a hydrogen atom means, one can also use biphenylene <§er general formula XXVIH

XXVIII

by reaction with dichloromethyl alkyl ethers, for example dichloromethyl butyl ether, in the presence of titanium (IV) chloride according to the method of A. Rieche, H. Gross and E. Höft, Chem. Ber. 9J, 88 - 9H (I960) manufacture.

For example, the following were obtained:
2'-Fluoro-il-biphenylcarboxaldehyde, F. H2 - 43 ° C,

2-fluorine-4-biphenylcarboxaldehyde, Sdn _{Q 1}

S'-chloro-1J-biphenylcarboxaldehyde, mp 65-66 ° C;

^Sd ^ 0.2 mmHg ^{li | n} ">

2-chloro- ⁱ l-biphenylcarboxaldehyde, an oily liquid at room temperature, was used without purification by distillation.

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Compounds of the general formula X are based on information from P. Ramirez and S, Dershowitz, J. org. Chemistry 22 , 41 (1957) from phosphonium salts of the general formula XXIX,

Si

- C - (CH ₂ ) _n -

XXIX

in which X is a halogen atom, easily obtainable by the action of bases. The salts of the general formula XXIX are in turn obtained one by the action of haloketones of the general formula XXX

Hai - CH ₂ -C- (CH _{2) n} - CH, XXX

on triphenylphosphine.

The ketones of the general formula XI can be obtained in a simple manner from an appropriately substituted biphenyl by reaction with acetyl chloride or propionyl chloride in the presence of anhydrous aluminum chloride _{, provided that R 1 and Rp are not different from one another or R ^ is a hydrogen atom.}

The starting compounds of the general formula XI, in which R2 is a what s only off atom, are, for example, from 3 '-halogen- ¹ ! - Amino-aceto (or-propio-) phenones by diazotization and subsequent reaction with benzene in the presence of sodium hydroxide solution

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or sodium acetate. Thus, for example, 4-acetyl-2-chloro-biphenyl melting point of 42-44 ⁰ C and Kp.

manufactured. However, these starting compounds can also be synthesized by reacting methyl magnesium halides with suitable 4-cyano-2-halobiphenyls and subsequent hydrolysis of the ketimine magnesium halides formed. In this way, for example, 4-acetyl-2-fluoro-biphenyl with a melting point of 97 98 ^° C. was obtained.

The starting compounds of the general formula XII can be obtained from suitable acetoacetic esters and orthoformic esters in the presence of catalytic amounts of sulfuric acid, according to the information provided by EE Smissman and AN Voldeng, J.org.Chemistry 29 3 316I (1964).

The new compounds of the general formula I have valuable pharmacological properties, in particular they have a good anti-inflammatory effect.

It were taking into account their absolute anti-inflammatory For example, the following substances were investigated for their effectiveness and toxicity:

A = (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol

B = 4- (2-fluoro-4-biphenylyl) -2-butanol

C = 8- (2'-fluoro-4-biphenylyl) -2-octanol

D = 6- (2'-fluoro-4-biphenylyl) -2-hexanone

E = 4- (4-biphenylyl) -2-pentanone

F = 8- (2'-fluoro-4-biphenylyl) -2-octanone

G = (E) -4- (4-biphenylyl) -3-penten-2-one

H = (E) -4- (2'-fluoro-4-biphenylyl) -3-penten-2-one

I = 4- (2-fluoro-4-biphenylyl) -2-pentanol

K = (E) -4- (2'-fluoro-4-biphenylyl) -3-penten-2-ol

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The substances were compared with phenylbutazone on theirs

anti-exudative effect "against kaolin edema and carra-

geeninedema of the rat hind paw as well as its acute toxicity

oral administration to the rat.

a) Kaolin edema of the rat hind paw:

Took place the release of the edema as indicated by HILLEBRECHT (drug Porsch. 4_, 607 (195 ¹ O) by the subplantar injection of 0.05 ml of a suspension above! Kaolin in O, $ 85 NaCl Lb "solution. The paw thickness was measured using the technique indicated by DOEPPNER and CERLETTI (Int. Arch. Allergy Immunol. Jj2, 89 (1958)).

Male PW 49 rats weighing 120-150 g were given the substances to be tested 30 minutes before the edema is triggered by a pharyngeal tube. 5 h after the edema provocation, the mean The swelling values of the animals treated with the test substance were compared with those of the sham-treated control animals. By graphical extrapolation, the dose was determined from the percentage inhibition values achieved with the various doses, which led to a lessening of the swelling (ED ,, -).

b) carrageenin edema of the rat hind paw:

The edema was triggered according to the information provided by WINTER et al. (Proc. Soc. Exp. Biol. Med. 111, 5 ^ 4 (1962)) the subplantar injection of 0.05 ml of a 1% solution of carrageenin in O.85 # NaCl solution. The test substances were 60 Administered min. before the edema provocation.

Purely the evaluation of the edema-inhibiting effect was the 3 h after The measured value obtained was used to induce edema. The other details corresponded to those described for kaolin edema.

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c) Acute toxicity:

The LDr- _n was determined after oral administration to male and female (equal parts) PW 49 rats with a mean weight of 135 g. The substances were administered as a trituration in Tylose.

As far as possible, the LD was calculated according to LITCH ^ IELD and WILCOXOM from the percentage of animals after the different Doses died within 14 days.

d) The therapeutic index as a measure of the therapeutic range was determined by forming the quotient of the oral LD ^ ₀ in the rat and that in the test for an anti-exudative effect (mean value from the kaolin edema and carrageenin edema test) in the rat ED ^ q calculated.

The results obtained from these tests are shown below Table put together.

The compounds mentioned outperform the well-known phenylbutazone in their desired antxphlogistic effect.

Since the toxicity is not parallel to the inflammatory effect experiences an increase, the claimed compounds outperform the phenylbutazone in their therapeutic index by the Pactor 2 or more.

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substance Kaolin edema Carrageenin
edema middle
value acute Toxicity Rat Therapeutic index KJ Phenyl
butazon ED ,, - per os
mg / kg ED ,, _ per os
mg / kg ED ₃₅
mg / kg mg / kr. Confidence Limits
at 95 percent True
probability Relationship between
toxic and anti-sexual
dative effect 2589 A.
B. 58 69 63.5 864 793-942 13.6 C. 15th
16 10
9.5 12.5
12.75 > 2400
I960 (0 out of 10 animals
deceased)
1441-2666 154 _% D. 15th 17th 16 760 618-935 ^ 7.5 T E. 9 10.5 9.75 965 661-1409 99 P. 21 15th 18th 1120 941-1333 62 G 9.8 14.5 12.15 785 609-1013 64.6 H
I. .23.5 8.6 K 37
17th 11
16.5 17.5 17th

The following examples are intended to explain the invention in more detail:

example 1

(E) - * <- (2'-Fluoro-4-biphenylyl) -3-buten-2-one

In a 6-1 three-necked flask with stirrer, dropping funnel and internal thermometer put 200.2 g (1.0 mol) of 2'-fluoro-4-biphenylcarboxaldehyde, 3500 g (60.3 mol) of acetone and 200 ml of methanol. The solution of 2.805 g is added dropwise to this solution with thorough stirring (0.05 mol) of potassium hydroxide in 16 ml of water, maintaining a reaction temperature of 20 to 25 ° C. Then another 3 hours stirred, the solid deposited by-product filtered off, the filtrate made neutral by dropwise addition of glacial acetic acid and evaporated in vacuo.

The remaining residue is uracrystallized three times from diisopropyl ether and once from a mixture of ethyl acetate and diisopropyl ether (volume ratio 1: 1) using activated carbon. The pale yellow crystals melt at 113-H ¹ J ⁰ C. The yield is 101.2 g (42 % of theory).

Example 2

(E) -4- (2'-chloro-4-biphenylyl) -3-buten-2-one

Prepared analogously to Example 1 from 2'-chloro-4-biphenylcarboxaldehyde and acetone in a yield of 56 % of theory. The pale yellow crystals melt after recrystallization from diisopropyl ether using activated charcoal at 124-125 ° C.

Example 3 (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-one

Prepared analogously to Example 1 from 2'-fluoro-4-biphenylcarboxaldehyde and acetone in a yield of 31 % of theory. The pale yellow

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Crystals melt after three recrystallizations from diisopropyl ether at 82 ~ 83 ° C.

Example M

(E) -M- (2 ^f -Fluoro-4-bipheny IyI) -3 ° buten_ ^ 2 ^ on

10.0 g (0.05 mol) of 2'-fluoro-4-biphenylcarboxaldehyde, 290 g (5.0 mol) of acetone and 2.05 g (0.025 mol) of zinc oxide are in the autoclave for 8 hours under nitrogen and a pressure of 70 at heated to 180 ° C. After cooling, the catalyst is filtered off _} the filtrate is concentrated in vacuo. The remaining residue is recrystallized once from ethanol and twice from diisopropyl ether, after which the pale yellow crystals melt at 113-H4 ° C. The yield is 7.30 g (61 % of theory),

Example 5 (E) -l- ( ^2f -fluoro-4- biphenyl) -l-hexen ° 3-one.

Prepared analogously to Example 4 from 2'-fluoro- ⁱ l-biphenylcarboxaldehyde with 2-pentanone in a yield of 56 % of theory. The pale yellow crystals melt after recrystallization from cyclohexane at 52-53 ° C.

Example 6

• (E) -4- (2 ^t fluoro-4-biphenylyl) -3-buten-2-'on

: In a mixture of 10.0 g (0.05 mol) of 2'-fluoro-4-biphenylcarbox-

• aldehyde and 290 g (5.0 mol) of acetone are introduced while maintaining a temperature of -20 to -15 ° C dry hydrogen chloride until saturation. The solution turns red. Stirring is continued for 2 days at room temperature for _#, the dark product dissolved in 2 1 ether and washed three times with water, once daijn proc-2 with. Caustic soda, finally again with water. It is dried with sodium sulfate and the solution is treated with activated charcoal. The solvent is imί

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jVacuum evaporated, the residue recrystallized three times from diisopropyl ether using activated charcoal. This gives 5.41 g (45% of theory) of pale yellow crystals of melting point 113-114 ⁰ C.

Example 7 (E) -4- (2-chloro-4-biphenylyl) -3-buten-2-one

Prepared analogously to Example 6 from 2-chloro-4-biphenylcarboxaldehyde and acetone in a yield of 52 % of theory. The pale yellow crystals melt after recrystallization from ethanol at 70 - 71 ° C.

Example 8

(E) -M- (2-fluoro-4-biphenylyl) -3-buten-2-one

A mixture of 38.0 g (0.19 mol) of 2-fluoro-4-biphenylcarboxaldehyde, 78.5 g (0.247 mol) of triphenylphosphine acetylmethylene and 200 ml of anhydrous tetrahydrofuran is refluxed for 5 hours. The solvent is distilled off and the remaining residue is boiled in a little ethanol to separate off the triphenylphosphine oxide formed as a by-product. It is allowed to cool, the crystals obtained are filtered off with suction and recrystallized twice more from ethanol for further purification. The yield of pale yellow crystals with a melting point of 83 ° C. is 40.2 g (88 % of theory).

Example 9 (E) -4- (2-chloro-4-biphenylyl) -3-buten-2-one

Prepared analogously to Example 8 from 2-chloro-4-biphenylcarboxaldehyde and triphenylphosphine acetylmethylene in a yield of 80 % of theory. The pale yellow crystals melt after recrystallization from ethanol at 70 - 71 ° C

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Example 10 j (E) -4- (2'-chloro-4-biphenylyl) -3-buten -2-one

, Prepared analogously to Example 8 from 2'-chloro-4-biphenylcarboxaldehyde and triphenylphosphine acetylmethylene in a yield of 81 % of theory. The pale yellow crystals melt after recrystallization from a mixture of diisopropyl ether and ethyl acetate (volume ratio 2: 1) at 124-125 ° C.

Example 11

(E) -4- (2-Fluor-4-biphenylyl) -3-penten-2-one

To a solution of 97.0 g (0.453 mol) of 4-acetyl-2-fluoro-biphenyl and 103.0 g (0.651 mol) of (E) -3-Ä "thoxy-crotonic acid ethyl ester in 1 l of anhydrous dimethylformamide are added all at once 72.8 g (0.649 mole) of potassium tert-butoxide, and the temperature rises spontaneously from +20 to +38 ⁰ C and the mixture is colored intensely red. the mixture is stirred an additional hour while maintaining a temperature of 32 to 35 ° C , 200 ml of concentrated hydrochloric acid are then added dropwise to the still warm batch and the mixture is ^{heated to a temperature of 90 to 100 ° C. for 30 minutes.} from impact, it is washed with water thoroughly and crystallized = him using activated charcoal once from methanol and ^twice. Diisopropylather times from order to give the pale yellow crystals

with a melting point of 103 ° C. in a yield of 75.0 g (65 % of theory).

^! Example 12 (E) -4- ( ^2f -chloro-4- biphenyl) -3- penten-2-one

Prepared analogously to Example 11 from 4-acetyl-2'-chlorobiphenyl and (E) = 3 ⁼ ethoxy-crotonic acid ethyl ester in a yield of 50 % of theory. After recrystallization from cyclohexane and petroleum ether

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The pale yellow crystals melt at 80 - 8l ° C.

Example 13 (E) - * t- (H-biphenylyl) -3-penten-2-one

Prepared analogously to Example 11 from 4-acetyl-biphenyl and (E) -3-ethoxy-crotonsäureäthylester in a yield of 62% of theory The pale yellow crystals melt at 130-132 ⁰ C (isopropanol).

example lH

(E) - ^ - (2 ^> -Pluoro-4-biphenylyl) -3-buten-2-one

To a suspension of 0.2 mol of lithium amide in 300 ml of anhydrous liquid ammonia, a solution of 15.8 g (0.1 mol) of (E) -3-ethoxy-crotonic acid ethyl ester in 20 ml of dry ether is added, whereupon the mixture is stirred for 10 minutes . Then a solution of 20.02 g (0.1 mol) of 2 ^f -fluoro-4-biphenylcarboxaldehyde in 20 ml of absolute ether is added dropwise, the mixture is stirred for 1 hour at the temperature of the boiling ammonia and then the ammonia is expelled by careful warming away. To the residue is added 200 ml of dimethylformamide and 100 ml of concentrated hydrochloric acid and the mixture heated with stirring for ¹ JO minutes at 100 ⁰ C. The cooled mixture is stirred into 500 ml of ice water, the yellowish precipitate abgenutseht, washed with water and recrystallized from cyclohexane and Diisopropylather . 14.8 g (62 % of theory) of pale yellow crystals with a melting point of 113 - H ¹ I ⁰ C. are obtained.

Example 15 2) - (2 «-piuoro-4-biphenylyl) -2-pentanone

A solution of 25.7 g (0.15 g) is added dropwise over the course of 1 hour to a methyl magnesium iodide solution, prepared from 12.2 g (0.5 mol) of magnesium and 71 g (0.5 mol) of methyl iodide in a total of 400 ml of anhydrous ether. 1 mol) 3- (2 ^f -fluoro-4-biphenylyl) -butyramide in 750 ml

509828/1037

dry methylene chloride and then refluxed for 6 hours to complete the reaction. The cooled batch is stirred into a mixture of 2 kg of ice and 100 ml of concentrated sulfuric acid, the organic phase is separated off, washed twice with water, then with saturated sodium hydrogen carbonate solution, finally again with water, dried over anhydrous magnesium sulfate and evaporated them in a vacuum. The solid residue is recrystallized twice from petrol, after which the colorless crystals at 60 (bp 60 to 80 ° C.) - 61 ⁰ C melt. The yield is 22.0 g (86 % of theory).

Example 16 4- (2 ^f -chloro-4-biphenylyl) -2-pentanone

Prepared analogously to Example 15 from 3- * (2 '~ chloro-4-biphenylyl) -butyramide and methylmagnesium iodide in a yield of 78 % of theory. The colorless, highly viscous oil boils at bp ~ ~, _TT 134 -

'0.0; mmHg ^J

137 ° C.

Example 17

2- (2'-fluoro-4-bi phenylyl ) -4-heptanone

Prepared analogously to Example 15 from 3 "(2'-fluoro-4-biphenyIyI) -butyramide and n-propyl magnesium bromide in a yield of 85% of theory The colorless, highly viscous oil boiling at bp _{n oi} -.."

0.0 mmHg

133 - 135 ⁰ C.

Example 18

(E) -4- (2'-fluoro-4frbiphenylyl) -3-penten-2-one

To a Grignard reagent made from 12.2 g (0.5 mol) of magnesium and 71 g (0.5 mol) of methyl iodide in 500 ml of anhydrous ether, a solution of 23.7 g (0.1 ; Mol) 3- (2'-fluoro-4-biphenylyl) -crotononitrile in 500 ml of dry

509828/1037

Methylene chloride, then heated under reflux for a further 4 1/2 hours and stirred the cooled batch in a mixture of 2 kg of ice and 100 ml of conc. Sulfuric acid. The organic layer is separated, with 1 percent. aqueous sulfuric acid, water, saturated sodium hydrogen carbonate solution and washed again with water, dried over sodium sulfate and concentrated in vacuo. The remaining solid residue is recrystallized from cyclohexane, after which the pale yellow crystals melt at 92.degree. The yield is 7.2 g (28 % of theory).

Example 19 4- (2'-fluoro-4-biphenylyl) -2-butanol

In the Grignard reagent, prepared in the complete exclusion of atmospheric oxygen, from 47.0 g (0.168 mol) of 1-bromo-2- (2'-fluoro-4-biphenylyl) -ethane and 4.0 g (0.165 mol) of magnesium in 60 ml of anhydrous ether is added dropwise with stirring the solution of 5> 82 g (0.132 mol) of acetaldehyde in 10 ml of dry ether. All operations are carried out under Entry tick off. When the addition is complete, the mixture is heated for a further 2 hours on the water bath with stirring, cooled, hydrolyzed by adding 50 g of crushed ice and then so much semi-concentrated hydrochloric acid is added that the resulting precipitate just dissolves. The ethereal layer is separated off, the aqueous phase is extracted twice more with ether and the combined extracts are washed with water, saturated sodium hydrogen carbonate solution and again with water. After drying over sodium sulfate, the ether is distilled off and the residue is recrystallized twice from petroleum ether using activated charcoal. The desired product is obtained in the form of colorless crystals with a melting point of 59-60 ° C. and in a yield of 9> 0 g (28 % of theory).

Example 20 1- (2'-chloro-4-biphenylyl) -3-hexanol

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Analogously to Example 19, the Grignard reagent is made from 35 ₉ 0 g (0.118 mol) of 1-bromo-2- (2'-chloro-4-biphenylyl) ethane and 2.9 g (0.119 mol) of magnesium with 13.35 g (0.185 mol) of butyraldehyde reacted in absolute ether. The resulting mixture of 1- (2'-chloro-4-biphenylyl) -3-hexanol and 1- (2'-chloro-4-biphenylyl) -3-hexanone (31 g, about 91 % of theory) is in 1 Dissolved 1 ethanol and after adding a solution of 2.10 g (O ₉ O56 mol) of sodium borohydride in 300 ml of ethanol

Stirred for 1 hour at room temperature. The excess sodium borohydride is decomposed by adding 3 ml of glacial acetic acid, the mixture is then evaporated, the residue is taken up in 500 ml of water, after which it is extracted exhaustively with ether. The combined ether extracts are dried over sodium sulfate and concentrated; evaporates, the residue is taken up in petroleum ether and chromatographed on a total of: 1 kg of silica gel using a mixture of petroleum ether and ethylene chloride (volume ratio 1: 1) ₂ , later of ethylene chloride / ethyl acetate (volume ratio 8: 2) for elution. The main product is taken up in ether, the ^ether: solution treated with activated carbon and again evaporated. The desired 1- (2'-chloro-4-biphenylyl) -3-hexanol is obtained as a colorless oil in a yield of 8.70 g (26 % of theory).

! Example 21

6- (4-BiphenyIy1) -2-hexanol

Prepared analogously to Example 20 _s, but without a final column chromatographic purification being necessary, from the Grignard reagent of 84.0 g (0.29 mol) 1- (4-biphenylyl) -4-bromobutane and 708 g (0.291 mol ) Magnesium and 14.2 g (0.32 mol) of acetaldehyde and subsequent reaction with sodium borohydride. The colorless crystals with a melting point of 62-63 ° C. (petroleum ether) are obtained in a yield of 38 * 0 g (44 % of theory).

Example 22

6- (2'-fluoro-4-biphenylyl) "2-hexanol

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Prepared analogously to Example 20 from the Grignard reagent of 1-bromo-4- (2'-fluoro-4-biphenylyl) butene and magnesium and acetaldehyde in an amount of 29 % of theory. The colorless crystals melt after chromatography on silica gel using benzene / ethyl acetate (volume ratio 9δ: 2) for the elution and recrystallized twice from petroleum ether at 52 - 53 ⁰ C

Example 23

8- (2'-Fluoro-4-biphenyly1) -2-octanol

Prepared analogously to Example 20 from the Grignard reagent of 1-bromo-6- (2 ^t -fluoro-4-biphenylyl) -hexane and magnesium and acetaldehyde in a yield of 42 % of theory. The colorless crystals melt at 64-65 ⁰ C (petroleum ether).

Example 24 12- (4-Biphenylyl) -2-dodecanol

Prepared analogously to Example 20 from the Grignard reagent, which was obtained from 1- (4-biphenylyl) -10-bromo-deean and magnesium, with acetaldehyde in a yield of 69 % of theory. The colorless crystals melt at 84-85 ⁰ C (petroleum ether).

Example 25

4- (2'-fluoro-4-biphenylyl) -2-pentanol

96.9 g (0> 4 mol) of 3- (2'-fluoro-4-biphenylyl) butanal (boiling point _{Q Qi | mmHK} ¹¹² - 114 ⁰ C), dissolved in the same volume of anhydrous ether, after the addition is complete, heated with stirring on the water bath for 2 hours, cools down, hydrolyzes by adding 50 g of crushed ice and then gives as much 50 percent. aqueous ammonium chloride solution to ensure that the initially

509828/1037

! the precipitate dissolves. The ethereal layer is separated off, the aqueous phase is extracted twice more with ether; the combined extracts are washed thoroughly with water. After drying over sodium sulfate, the ether is distilled off and ^; the remaining residue is distilled in a fine vacuum. The desired 4- (2'-fluoro-4-biphenylyl) -2-pentanol is obtained in the form of a mixture of diastereomers and as a colorless oil with bp. _R , ^ r _TT

¹ 0.06 mmHg

122-124 ° C in a yield of 55.8 g (54 % of theory).

Example 26

4- (2'-fluoro-4-biphenylyl) -2-butanone

In a hydrogenation pear, 15 g (0.06 mol) of nickel (II) acetate tetrahydrate, dissolved in 600 ml of 95 percent strength, are dissolved in a hydrogen atmosphere. Ethanol, reduced to black, colloidal nickel boride (P-2 catalyst) with 60 ml of 1 M sodium borohydride solution. In order to remove any unused borohydride, 14 g (0.24 mol) of acetone are first added, the mixture is shaken for 1 hour at room temperature and, after the addition of 30.0 g (0.123 mol) of (E) -4- (2-fluorine-4), hydrogenated -biphenylyl) -3 ~ buten-2-one at 5 atm. hydrogen pressure until the hydrogen uptake ceases. The catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is partitioned between water and ethyl acetate, the organic phase is dried over sodium sulfate and evaporated, the residue is distilled in a fine vacuum. This gives 18.5 g (62% of theory) of a colorless, viscous than the boiling point _Q ^ _mm Hp ^1. 53 - 155 ° C which solidifies on prolonged standing. Melting point: 30 ⁰ C.

Example 27 4- (2 ^> -Fluoro-4-biphenylyl) -2-butanol

24.5 g (0.101 mol) of (E) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-ol, dissolved in 300 ml of ethyl acetate, at room temperature and 3 atm hydrogen pressure and in the presence of 8.5 g of Raney nickel up to Termination of hydrogen uptake hydrogenated. It is filtered from the ca

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catalyst, the piltrate evaporated in vacuo and the residue crystallized from cyclohexane / petroleum ether (volume ratio 1: 1) twice. 15.0 g (61 % of theory) of colorless crystals with a melting point of 59 ° -60 ° C. are obtained.

Example 28 4- (2 ^f -chloro-4-biphenylyl) -2-butanol

Prepared analogously to Example 27 from (E) -4- (2'-chloro-4-biphenylyl) -3-buten-2-ol in a yield of 33 %. The product was obtained as a colorless, non-crystallizing oil and purified by chromatography on silica gel using initially benzene and later benzene / ethyl acetate (volume ratio 9: 1) for the elution. The characterization was carried out by IR, UV and NMR spectra as well as by elemental analysis:

C ₁₆ H ₁₇ ClO (260.8) calc. C 73.70 H 6.57 Cl 13.60

Found C 73.70 H 6.70 Cl 13.30

Example 29

4- (2-fluoro-4-biphenylyl) -2-butanol

Prepared analogously to Example 28 from (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol in a yield of 89 % of theory. After recrystallizing twice from gasoline, the colorless crystals melt at 40-42 ° C.

Example 30 4- (2-fluoro-4-biphenylyl) -2-pentanone

Prepared analogously to Example 26 from (E) -4- (2-fluoro-4-biphenylyl) -3-penten-2-one in a yield of 80 % of theory. The colorless crystals melt at 85-86 ⁰ C (Diisopropylather).

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Example 31 4- (2-fluoro-4-biphenylyl) -2-butanone

Prepared analogously to Example 26 from (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-one in a yield of 62 % of theory. The colorless crystals melt after two recrystallization from gasoline ■ at 41 - 42 ° C.

Example 32 4- (2-chloro-4-biphenylyl) -2-butanone

Prepared analogously to Example 26 from (E) -4- (2-chloro-4 - biphenylyl). -3-buten-2-one in a yield of 68% of theory as a colorless, highly viscous oil of boiling _{n nR} "^ "" 148 - 153 ° C.

! Example 33 ^: 4- (2-fluoro-4-biphenylyl) -2-pentanol

ι -

: Prepared analogously to Example 28 from (E) -4 = (2-fluoro-4-biphenylyl) -3-

penten-2-ol in a yield of 45 % of theory »The colorless j crystals melt after recrystallization from petroleum ether: using activated charcoal at 53 - 54 ° C. According to H-NMR spectros-

After a copy examination, only one of the two possible diastereomers is present. A non-crystallizing mixture of the two diastereomers (colorless, highly viscous oil) can be isolated from the mother liquors in a yield of again 29 % of theory.

Example 34 ^{1- (2 f} -Fluoro-4-biphenylyl) -3-hexanone

Prepared analogously to Example 26 from (E) -I- (2'-fluoro-4-biphenyIyI) -l-hexen-3 ~ one in a yield of 74 % of theory. The colorless,

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Highly viscous, non-crystallizing oil was purified by column chromatography on silica gel and characterized by IR, UV and NMR spectra and by elemental analysis. C ₁₈ H ₁₉ PO (270.35) calc. C 79.97 H 7.08

Found C 79.90 H 7.10

Example 35

4- (2'-fluoro-4-biphenyIy1) -2-pentanone

2.5 ^ 3 E (0.01 mol) (E) -4- (2 ^l -Pluoro-4-biphenylyl) -3-penten-2-one are dissolved in 50 ml of benzene in the presence of 0.5 g of 5- percent Palladium on calcium carbonate is hydrogenated in a Parr apparatus at room temperature and 5 atm. Hydrogen pressure up to the absorption of 0.01 mol of hydrogen. The catalyst is filtered off, the filtrate is concentrated in vacuo and the remaining residue is purified first by chromatography on silica gel, then by recrystallization twice from gasoline. 1.87 g (73 % of theory) of colorless crystals with a melting point of 60 are obtained up to 61 ⁰ C.

Example 36

(E) -4- (4-biphenylyl) -3-buten-2-ol

13.0 g (0.0585 mol) of (E) -4- (4-biphenylyl) -3-buten- | 2-one with 12.5 g ( 0.0612 mol) aluminum isopropylate and 190 ml (2.48 mol) isopropanol under gentle reflux, so that only about 5 drops distill off per minute. After about 5 hours -in the distillate with hydrochloric acid 2. ^i! -Dinitrophenylhydrazin solution no! Acetone longer detectable in the reaction mixture by thin layer chromatography showed no starting material. The isopropanol is under! Slight vacuum distilled off, the residue was hydrolyzed by addition of 6N ■ J50 g cracked ice and 3 ml of hydrochloric acid ¹ J. It is exhaustively extracted with ethyl acetate, and the combined extracts are washed with water, 5 percent strength. Sodium hydroxide solution and again water. Dries them over sodium sulfate and the solvent evaporates in vacuo

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Iab and recrystallizes the residue once from cyclohexane / ethyl acetate (volume ratio 9: 1) and once from benzene. 11.0 g (84 % of theory) of colorless crystals with a melting point of 138-139 ° C. are obtained.

Example 37 (E) -4- (4-Biphenylyl) -3-buten-2-ol

"22.2 g (0.1 mol) of (E) -4- (4-biphenylyl) -3-buten-2-one, dissolved in ^1: 95 percent strength ethanol, are added portionwise within 10 minutes, at a. A solution of 1.9 g (0.05 mol) of sodium borohydride in 300 ml; 95% strength ethanol is added. The mixture is then stirred for 1 hour at room temperature. The excess reducing agent is destroyed by carefully adding 3 g of glacial acetic acid. 500 ml of water are added to the residue, then extracted exhaustively with ether, the combined ether extracts are washed with water, dried over sodium sulfate and evaporated. The residue is obtained from ethyl acetate / petroleum ether (volume ratio 1: 9) using 16.1 g (72 % : of theory) of colorless crystals with a melting point of 138-139 ° C., according to thin-layer chromatography, melting point, mixed melting point and spectra, completely identical to a preparation obtained according to Example 36 are obtained.

Example 38 ■ 4- (4-Biphenylyl) -2-butanol

Prepared analogously to Example 37 from 4- (4-biphenylyl) -2-butanone in a yield of 79 % of theory. The colorless crystals melt after two recrystallizations from cyclohexane at 73 - 74 ^° C.

. Example 39

( _E ) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-ol

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Prepared analogously to Example 36 from (E) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-one in a yield of 77 % of theory. After purification by column chromatography on silica gel using benzene as the eluent and recrystallization from diisopropyl ether and cyclohexane, each using activated charcoal, the colorless crystals melt at 98-99 ° C.

Example 40 (E) -4- (2'-Fluoro-4-biphenylyl) -3-buten-2-ol

Prepared analogously to Example 37 from (E) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-one in a yield of 41 % of theory. After recrystallizing twice from diisopropyl ether using activated charcoal, the colorless crystals melt at 98-99 ° C.

Example 41 4- (2 ^t -chloro-4-biphenylyl) -2-butanol

Prepared analogously to Example 37 from 4- (2'-chloro-4-biphenylyl) -2-butanone in a yield of 33 % of theory. After chromatography on silica gel, the compound was obtained in the form of a colorless, viscous oil and characterized by IR, UV, H-NMR spectra and elemental analysis.

C ₁₆ H ₁₇ ClO (260.8) calc. C 73.70 H 6.57 Cl 13.60

Found C, 73.60 H 6.71 Cl 13.73

Example 42 (E) -4- (2'-Chloro-4-biphenylyl) -3-buten-2-ol

Prepared analogously to Example 37 from (E) -4- (2'-chloro-4-biphenylyl-3-buten-2-one in a yield of 95 % of theory. The colorless crystals melt after recrystallization from diisopropyl ether / petroleum ether ( Volume ratio 1: 2) and cyclohexane at 64 to 65 ⁰ C.

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Example 43 (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol

j Prepared analogously to Example 37 from (E) -4- (2-fluoro-4-biphenylyl) -13-buten-2-one in a yield of 88 % of theory. The colorless * crystals melt after three recrystallization from cyclo- 'hexane at 107-108 ° C.

! Example 44 4- (2-chloro-4-biphenylyl) -2-butanol

¹ Prepared analogously to Example 37 from 4- (2-chloro-4-biphenylyl) -2-butanone in a yield of 78 % of theory. After chromatography on silica gel, the product became a colorless, viscous, non-crystallizing oil (R _p 0.60 _s Merck TLC pre-fabricated silica gel plates | 60 pp ^t 54 ⁱ layer thickness 0.25 mm; benzene / ethyl acetate in volume ratio 1: 1 as eluent), which was characterized by IR, UV, ■ NMR spectra and by elemental analysis. : C ₁₆ H ₁₇ C 10 (260.8) calc. C 73.70 H 6.57 Cl 13.60 ί Found: C 73.50 H 6.7 ^ Cl 13.38

j Example 45

| (E) -4- (2-fluoro-4-biphenylyl) -3-penten-2-ol

I '
I.

'Prepared analogously to Example 36 from (E) -4- (2-fluoro-4-biphenylyl) -j3-penten-2-one in a yield of 88 % of theory. The colorless crystals melt after recrystallization from diisopropyl ether at 98 ^° C.

I ■! Example 46

1 4- (2'-chloro-4-biphenyIyI) -2-pentanol

! Prepared analogously to Example 37 from 4- (2'-chloro-4-biphenylyl) -2-

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pentanone in a yield of 93 % of theory. The colorless, viscous, non-crystallizing oil, consisting of a mixture of the two possible diastereomers, could be removed by distillation

Clean ilation in a fine vacuum: Sdp._ _ ,. "126 - 128 ° C. ι 0.0h mmlig

: ^C 17 ^H 19 ^C1 ° ( ²⁷ M) ^Ber - ^c 74.31 H 6.97 Cl 12.90 I found C 7h, hO H 7.06 Cl 12.70. -

Example 46

; 4- (2 ^f -fluoro-4-biphenyIyI) -2-pentanol \

Prepared analogously to Example 37 from 4- (2 * -fluoro-4-biphenyIyI) -2-pentanone in a yield of 83 % of theory. The colorless, viscous oil, consisting of a mixture of the two possible diastereomers, boils at bp ~ _ne: “122 - 124 ° C. ; 0.0b mmfig

' Example 47 ^: 2- (2 ^> -Fluoro - ^ - biphenylyl) -4-heptanol

To a suspension of 1.0 g (0.0264 mol) of lithium aluminum hydride in 50 ml of anhydrous ether is added dropwise within 90 minutes a solution of 15.5 g (0.0545 mol) of 2- (2'-fluoro-4-biphenylyl ) -4- [ iheptanone in 600 ml of dry ether, stirred for 45 minutes at room temperature and then refluxed for 4 hours. Under

I ι

■ External cooling with an ice bath, 1 ml is then added dropwise one after the other ^! Water, 1 ml 15 percent Sodium hydroxide solution and another 2 ml of water are then filtered off from the precipitate and the filtrate is concentrated in vacuo. The oily residue, consisting of the two possible dia-; ■ jstereomers of 2- (2'-fluoro-4-biphenylyl) -4-heptanol, is distilled in a vacuum and has a _{boiling point of n 7} """1-245 ° C above. The yield is 15.1 g (97 % of theory).

Example 48

(E) -4- (2'-fluoro-4-biphenylyl) -3-penten-2-ol

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Prepared analogously to Example 37 from (E) -4- (2'-fluoro-4-biphenylyl) - • 3-penten-2-one in a yield of 73 % of theory. The coloring *

^! After recrystallization from cyclohexane, loose crystals melt at 86 ° C.

Example 49 (E) -4- (4-biphenylyl) -3-penten-2-ol

Prepared analogously to Example 37 from (E) -4- (4-biphenylyl) -3-penten-.2-one in a yield of 66% of theory. The colorless crystals melt after recrystallization from diisopropyl ether _: at 147 - 148 ^° C.

Example 50 ■ (E) -4- (2'-Chloro-4-biphenylyl) -3-penten-2-ol

Prepared analogously to Example 37 from (E) -4- (2-chloro-4-biphenylyl) -3-penten-2-one in a yield of 45 % of theory. The colorless, non-crystallizing oil = _Q g boiling at bp 148 _mmH -. 150 ⁰ C.

Example 51 4- (4-biphenylyl) -2-pentanol

Manufactured analogously to Example 37 from 4- (4-biphenylyl) -2-pentanone in a yield of 88 % of theory. The colorless crystals melt ■ at 58 - 60 ° C (cyclohexane). According to H-NMR spectroscopic investigations, only one of the two possible diastereoirs lies

Example 52

' 4- (2'-Fluoro-4-biphenylyl) -2-butanone
^! 25.0 g (0.104 moles) of (E) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-one _J.

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dissolved in 1500 ml of ethyl acetate, are hydrogenated at room temperature and 3 atm hydrogen pressure and in the presence of 10 g of Raney nickel until the hydrogen uptake slows down clearly. The catalyst is filtered off, the piltrate is evaporated in vacuo and the residue, consisting of a mixture of 4- (2 · fluoro-4-biphenylyl) -2-butanol and the desired 4- (2 ^f -fluoro-4), is dissolved -biphenylyl) -2-butanone, in a mixture of 155 ml of anhydrous dimethyl sulfoxide, 155 ml of dry benzene, 8.25 ml (0.102 mol) of pyridine and 4.15 ml (0.056 mol) of trifluoroacetic acid. 64.0 g (0.31 mol) of N.N'-dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 12 hours. The mixture is then diluted with 2.5 liters of ether, whereupon a solution of 39.08 g (0.31 mol) of oxalic acid dihydrate in 250 ml of methanol is added dropwise with stirring. After the evolution of gas has ceased, which lasts for about 30 minutes, 2.5 l of water are added and the insoluble N.N'-dieyclohexylurea is removed by filtration. The layers are separated and the organic phase is shaken twice at 5 ~ percent. Sodium hydrogen carbonate solution and once with water, dry it with sodium sulfate, filter and evaporate the solvent. The remaining oily residue, which still contains small amounts of dicyclohexylurea, is chromatographed on silica gel using benzene for the elution and distilled twice under fine vacuum. 5 g (50% of theory) of 12, the above-formulated ketone of boiling ^ ^ 153 -. 155 ° C or boiling ^ _mmHg l48 -. I ₅ O ⁰ C and a melting point of 3O ⁰ C (petroleum ether).

Example 53

6- (4-biphenylyl) -2-hexanone

A mixture of 6- (4-biphenylyl) -2-hexanone and 6- (4-biphenylyl) -2-hexanol obtained analogously to the Grignard reaction described in Example 21 is treated with dimethyl sulfoxide in the presence of N. Oxidized N'-dicyelohexylcarbodiimide and pyridinium trifluoroacetate. The 6- (4-biphenyl) -2-hexanone sought is obtained in a yield of 40 % of theory. The colorless crystals melt at 51 - 52 ° C (from gasoline and petroleum ether).

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2362583

. Example 54

; 6- (2 ^! -Fluoro-4-biphenylyl) -2-hexanone

: 20.0 g (0.0734 mol) 6- (2 ^! -Fluoro-4-biphenylyl) -2-hexanol are dissolved in a mixture of 110 ml of anhydrous dimethyl sulfoxide, 110 ml of absolute benzene, 5.9 ml (0.0732 Mol) pyridine and 2.95 ml (0.0397 mol) 'i-trifluoroacetic acid dissolved. 45.5 g (0.22 mol) of N.N'-dicycloihexylcarbodiimide are added and the mixture is stirred for 14 hours at room temperature. Then; if you dilute the mixture with 2 liters of dry ether, add dropwise ^! Stir a solution of 27.7 g (0.22 mol) of oxalic acid dihydrate in 180 ml of methanol and add 2 liters of water after the evolution of gas, which lasts for about 30 minutes. The insoluble N.N'-dicyclohexyl urea is filtered off, the aqueous and organic layers are separated and the organic phase is _s proc 5-twice with sodium bicarbonate solution and once overall with water;.. wash, and evaporated dried over sodium sulfate the remaining residue is chromatographed on silica gel using. benzene to elute chromatographed then recrystallized three times from petrol to give 7.0 g (35% of theory) of colorless crystals of melting point 37 -!.! 38 ⁰ C.

Example 55

^: 8- (2 * -Fluoro-4-biphenyIyI) -2-octanone

Prepared analogously to Example 54 from 8- (2'-fluoro-4-biphenylyl> -2- ■ octanol by oxidation with dimethyl sulfoxide in the presence of pyriidinium trifluoroacetate and N.N'-dicyclohexyl carbodiimide in a yield of 80 % of theory colorless crystals continue to melt, purification by column chromatography on silica gel using benzene / petroleum ether (volume ratio 9: 1) to elute and recrystallize from gasoline and gasoline / petroleum ether (volume ratio

! ί: 1) at 32 ° C.

50 9 8 28/1037

Example 56

4- (2'-chloro-4-biphenyIyI) -2-butanone

Prepared analogously to Example 54 from 4- (2'-chloro-4-biphenylyl) -2-butanol by oxidation with dimethyl sulfoxide in the presence of pyridinium trifluoroacetate and N.N'-dicyclohexyl-carbodiimide in a yield of 92 % of theory. The colorless crystals melt to säulenchromatographiseher purification on silica gel using benzene / petroleum ether (volume ratio 2: 1) for the elution and recrystallization from petroleum ether and ethanol at; 34 - 35 ⁰ C

Example 57 4- (2 -fluoro- ^{i t} l-biphenylyl) -2-pentanone

0, O ¹ Il ml (0.5 m mol) dichloroacetic be to an ice cold, stirred solution of 258 mg (1 m mol) of 4- <2'-fluoro-4-biphenylyl) -2-'pentanol (mixture of the two possible diastereomers) and 515 mg ^: (2.5 m mol) N.N'-dicyclohexyl-carbodiimide in a mixture of j5 ml of anhydrous dimethyl sulfoxide and 5 ml of absolute benzene. The mixture is stirred for 30 minutes at room temperature, then cooled to: 0 ° C. and a concentrated aqueous solution of 189 mg (1.5 m mol) of oxalic acid dihydrate is added. It is kept at room temperature for a further 20 minutes, diluted with 50 ml of ethyl acetate and filtered. The organic phase is washed five times with water, dried over sodium itrium sulfate and evaporated in vacuo. The 'residue is purified first by column chromatography on silica gel using benzene / petroleum ether (volume ratio 9: 1) to elute, then by recrystallizing twice from gasoline. Man! Obtains IJ ^ mg (68% of theory) -one as colorless crystals from the j melting point 60 to 6l ° C.

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- 53 - 2362583

Example 58 (E) -4- (2'-Fluoro-4-biphen ylyl) -3- penten-2-one

Prepared analogously to Example 11 from 4-acetyl-2'-fluoro-biphenyl and (E) -3-ethoxy-crotonic acid ethyl ester in a yield of 44 % of theory. The pale yellow crystals melt after recrystallization from isopropanol at 92-93 ° C.

Example 59

I (E) -l- (2'-fluoro-4-biphenylyl) -l -hexen-3-ol

Prepared analogously to Example 36 from (E) -l- (2'-fluoro-4-biphenylyl) -l-hexen-3-one in a yield of 87 % of theory. The colorless crystals melt after purification by column chromatography! Silica gel using methylene chloride for elution and after recrystallization from gasoline at 41 - 42 ° C.

Example 60 ^{1- (2 f} -Fluoro-4-biphenylyl) -3-hexanol

Prepared analogously to Example 27 from (E) -l- (2 ^l -fluoro-4-biphenylyl) -l-hexen-3-ol in a yield of 85 % of theory. The colorless, viscous, non-crystallizing oil was purified by column chromatography on silica gel using methylene chloride for the elution and characterized by IR, UV, H-NMR spectra and elemental analysis.

5C ₁₈ H ₂₁ PO (272.37) calc. C 79.38 H 7.77

Found C 79.50 H 7.90

Example 61

4- (2-fluoro-4-biphenylyl) -2-butanol
; To a solution of 2.423 g (0.01 mol) 4- (2-fluoro-4-biphenylyl) -2-

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butanone in 200 ml of 95 percent Ethanol is given to 2.40 g (0.06 mol) of sodium hydroxide, dissolved in 120 ml of water, then with stirring and in
small portions within 2 hours 3.244 g (0.03 mol) of thio- _: urea-S, S -dioxide, with a temperature of 80 to 90.degree
complies, and then refluxes for a further 2 hours. That; Ethanol is distilled off, the remaining aqueous solution is extracted exhaustively with ether, the combined extracts over Na- | Trium sulfate dried and evaporated. The crude product is dissolved in benzene and chromatographed on 100 g of silica gel, traces of starting material being separated off. Pure, colorless 4- (2-fluoro-4-biphenylyl) -2-butanol is obtained from the main fraction
! Melting point 40 - 42 ⁰ C (petrol) in a yield of 2.19 g (90 %
ι the theory). ^:

! Example 62 j

4- (2'-fluoro-4-biphenylyl) -2-butanol !

Prepared analogously to Example 61 from 4- (2'-fluorine-4-biphenylyl) -2-butanone in a yield of 93 % of theory. The colorless crime

Stalls melt at 59 - 60 ° C (cyclohexane / petroleum ether in the volume ratio 1: 1). ;

i!

' Example 63

j 4- (2'-fluoro-4-biphenyly1) -2-pentanone ;

! An externally electrically heated one filled with thorium dioxide
! Combustion tube made of Pyrex glass, 90 cm long and 2 cm in diameter, is heated to 430 to 450 ° C, carefully filled with carbon dioxide
: rinsed and then further rinsing with carbon dioxide via a A: laßkammer with a mixture of 258.3 g (1.0 mole) of 3- (2'-fluoro-4-jbiphenyIyI) butyric acid (melting point: 98 - 99 ⁰ C ) and 18o g (3.0 'mol) of acetic acid charged, with a rate of addition of; 115 drops per minute should not be exceeded. The whole
! Solution should pass the reaction tube in about 18 to 21 hours,
j After all of the reaction mixture has been added, the tube is

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rinsed with 10 ml of glacial acetic acid each time to completely remove the reaction product. Distillate and washing solutions are combined, mixed with 500 g of ice water and with a small excess of 50 percent. aqueous sodium hydroxide solution made alkaline. The oily product is separated off and the aqueous phase is extracted exhaustively with ether. The organic combined with the oil. Extracts are washed with water, dried over sodium sulfate and freed from the solvent. The residue is carefully chromatographed on a total of 5 kg of silica gel using initially benzene, later benzene / methylene chloride (volume ratio 1: 1) to elute in order to remove higher molecular weight by-products. After evaporation of the eluates and recrystallization from gasoline, 53.4 g (21 % of theory) of colorless crystals with a melting point of 60-61 ° C. are isolated.

! Example 64 ' 4- (2-fluoro-4-biphenylyl) -2-pentanone

Prepared analogously to Example 63 from 3- (2-fluoro-4-biphenylyl) butyric acid (melting point: 96-97 ° C.) and acetic acid in a yield of 15 % of theory. The colorless crystals melt at 85; 86 ° C (diisopropyl ether).

j Example 65

i 4- (2-fluoro-4-biphenylyl) -2-butanol

• To a solution of 25.3 g (0.105 mol) (E) -4- (2-fluoro-4-biphenylyl) -J3-buten-2-one 15.3 g (0.63 mol) of magnesium are added to 400 ml of anhydrous methanol and the reaction, which soon becomes lively, is carried out {Moderate water cooling so that the mixture does not reflux too violently. The metal disappears within 2 hours. A clear solution results, which is freed from methanol by distillation. Then 100 ml of ice water are added, 'then 80 percent Acetic acid to a weakly acidic reaction.

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The separated oil is taken up in ethyl acetate, the solution is washed with water, saturated sodium hydrogen carbonate solution and again with water, dried with sodium sulfate and evaporated. The remaining residue is recrystallized three times from gasoline, after which the colorless crystals melt at 40 to 42 ° C. The yield is 17.9 g (70 % of theory).

The same compound is obtained under the same reaction conditions in a yield of 76 % of theory if 4- (2-fluoro-4-biphenylyl) -2-butanone is used instead of (E) -4- (2-fluoro-4 -biphenylyl) -3-buten-2-one used.

example 66
4- (2 ^t -fluoro-4-biphenylyl) -2-butanol

Prepared analogously to Example 65 from (E) -4- (2 ^l -fluoro-4-biphenylyl) -3-buten-2-one in a yield of 72 % of theory. The colorless crystals melt after recrystallization from petroleum ether at | 59-60 ⁰ C.

Example 6 7

14- (2'-Fluoro-4-biphenyly1) -2-butanol

To a solution of 24.0 g (0.1 mol) of (E) -4- (2'-fluoro-4-biphenylyl) -; 3-buten-2-one in 1 l of anhydrous methanol are added in small portions 46.0 (2.0 mol) of freshly cut sodium, the 'lively reaction being moderated by external cooling to such an extent that. the mixture does not cook too vividly. After the metal has completely dissolved, most of the methanol is distilled off, 1 l of ice water is added to the residue, and the mixture is then mixed with acetic acid; weakly acidified. Las separated oil is taken up in üther, the solution with water, saturated sodium bicarbonate solution \ and again washed with water, dried and evaporated with sodium sulphate. The remaining residue is recrystallized twice from petroleum ether, after which the colorless crystals at 59 to

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Melting at 60 ° C. The yield is 18.1 g (74 % of theory).

' Example 68

■ 4- (2-fluoro-4-biphenylyl) -2-butanone

[16.44 g (0.0684 mol) of (E) -4- (2-fluoro-4-biphenylyl) = 3-buten-2-oen are dissolved in 200 ml of ethanol, for this purpose 250 ml of 20 percent strength are added. ! given aqueous ammonia. With constant heating, with partial separation occurring, 220 ml of 15 percent are gradually added. ; Titanium (III) chloride solution to _s whose rapid discoloration the one; ! indicates a reaction that occurs. After half an hour of warming, the titanium acid precipitate is sucked off, the piltrate is diluted with water and etherified. The titanium acid precipitate is also thoroughly extracted with jÄther. The combined ether solutions are dried over sodium sulfate, filtered and evaporated. The remaining residue is chromatographed on a total of 800 g of silica gel using benzene to elute, the thus purified product again ■ jaus gasoline recrystallized twice, after which the colorless crystals, at 41 - 42 ° C to melt. The yield is 6.9 g (42 % of the '■

Theory). ;

Example 69 -:

j4- (2'-fluoro-4-biphenylyl) -2-pentanone

Prepared analogously to Example 68 from (E) -4- (2'-fluoro-4-biphenylyl) -3-penten-2-one in a yield of 37 % of theory. The colorless crystals melt at 60 to 61 ° C (petrol).

Example 70

4- (2'-fluoro-4-biphenylyl) -2-butanone

A solution of 32.87 g (0.1368 mol) of (E) -4- (2'-fluoro-4-biphenylyl) -3 ~ buten-2-one 20 to 25 ml of 2 η sulfuric acid are added to 200 ml of glacial acetic acid until the cC-ß-unsaturated ketone has just separated

509828/1037

he follows. This mixture is in the cathode compartment with one. Electrolysis cell provided with a diaphragm and electrolyzed at 60 volts and 5 to 6 amps, the anode compartment with 20 percent. Sulfuric acid is filled. A 1 cm high layer of mercury serves as the cathode and a carbon rod as the anode. The strong heat development during electrolysis makes intensive internal and external cooling necessary. After 6 hours, most of the glacial acetic acid is evaporated off in a water-jet vacuum, the residue is neutralized with soda, and the mixture is then extracted with ether. A dimeric by-product precipitates and is filtered off with suction. From the ethereal extracts which are dried washed with water and dried over sodium sulfate, man.nach chromatographic purification on silica gel obtained using benzene to elute and distillation under high vacuum (bp _Q n nrou-150 -. 155 ° C) 6.92 g (21 % of theory) of color

loose crystals of melting point 30 ⁰ C (petroleum ether).

Example 71 j

i
^ - (2'-fluoro-4-biphenylyl) -2-butanone ·

With external cooling with ice, 1 (0.0342 mol) (E) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-one in 30 ml is added to a solution of 8.22 g | 'Ethanol 93 g (0.101 mol) 2.5 percent. Sodium amalgam together with small amounts of 50 percent. Acetic acid (a total of 15 mlj 0.125 mol), whereby:; Care must be taken to ensure that the mixture always reacts slightly acidic. The mixture is shaken vigorously during the amalgam addition, which takes about 1 hour, then left to stand overnight, diluted with water, neutralized with soda and; ! exhaustively extracted with ether. The combined and ^dried: jÄtherextrakte are evaporated, the remaining residue by careful chromatography on silica gel and Destil- 'jlation an oil pump | - cleaned (Sdp.Q jl53 155 ⁰ C). To yield the colorless, viscous oil, which solidifies 30 ⁰ C on trituration with petroleum ether to ¹ crystals of melting point, in a yield of:

3.65 g (44 % of theory). '■

509828/1037

i:

, Example 72

! ^ - (2-Fluoro-4-biphenylyl) ~ 2-butanone

8.22 g (0.03 ^ 2 mol) of (E) -4- (2-fluorine-4-biphenylyl) -3-buten-2-one are dissolved in 30 ml of ethanol, whereupon at temperatures between 80 and 100 ⁰ C 9.5 g analgamated zinc together with a total of 68 ml 50 percent. Acetic acid is added in portions over the course of 36 hours. ■ The cooled reaction mixture is then diluted with 500 ml of water and exhaustively extracted with ether. The evaporated ether extracts are carefully chromatographed on a total of 700 g of silica gel using benzene to elute di- ^! freed mer reaction products and starting material; the thus purified product is recrystallized again from gasoline _s after which the colorless crystals melting at 41 to 42 ° C. The yield is 124 g (15 % of theory).

Example 73

4- (2'-fluoro-4-biphenylyl) -2-butanol

To a mixture of 2.40 g (O ₉ Ol mol) (E) -4- (2'-fluorine-4-bi-: phenylyl) -3-buten-2-one, 10.7 g (0.2 Mol) ammonium chloride, 100 ml absolute ether and 100 ml liquid ammonia are added dropwise while maintaining a temperature of -40 ° C to the boiling point of the ammonia and with stirring a solution of 3.45 g (0.15 mol) najtrium in 150 ml liquid ammonia within 3 hours. After the ammonia has evaporated, 100 ml of water are added, the layers are separated and the aqueous phase is exhaustively extracted with ether. The combined ethereal solutions are dried and evaporated, the residue is chromatographed on silica gel using initially benzene and later benzene / methylene chloride (volume ratio 1: 1) to elute. The substance is obtained in the form of multicoat color white crystals of melting point 59-60 ⁰ C (cyclohexane / Petrolä'ther in the volume ratio 1: 1)!. The yield is 1.51 g (62 % of theory).

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The same compound is obtained under the same reaction conditions in a yield of 68 % of theory if 4- (2'-fluoro-4-biphenylyl) -2-butanone is used instead of (E) -4- (2 ^f - Fluoro-4-biphenylyl) -3-buten-2-one used.

example Ik

(E) -4- (2 ^f -fluoro-4-biphenylyl) -3-butene-2-o, l

A solution of 12.014 g (0.05 mol) of (E) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-one in 50 ml of anhydrous benzene is added dropwise while maintaining a reaction temperature of 5 to 15 ° C within 45 minutes a total of 7.22 g (0.025 mol) of a 70 percent. Solution of sodium bis (2-methoxy-ethoxy) dihydroaluminate in benzene, whereupon the mixture is stirred for a further 2.5 hours at the stated temperature. Then decomposed by careful, dropwise addition of 20 ml of 20 percent. Hydrochloric acid and stir for a further 20 minutes. The benzene layer is separated off and washed twice with 40 ml of water each time. The combined aqueous phases are extracted again with ml of ether. The ether extract is combined with the benzene phase, whereupon this solution is dried with sodium sulfate and evaporated. The residue is purified by column chromatography on silica gel using benzene as the eluent, then recrystallized once each from diisopropyl ether and cyclohexane. The colorless crystals with a melting point of 98 ° to 99 ° C. are obtained in a yield of 10.1 g (83 % of theory).

Example 75

' (E) -4- (2-fluoro-4-biphenylyl) -3-penten-2-ol

prepared analogously to Example 74 from (E) -4- (2-fluoro-4-biphenylyl) -3-

penten-2-one in a yield of 76 % of theory. The colorless! Crystals melt after purification by column chromatography on jKieselgel and recrystallization from diisopropyl ether at 98 ⁰ C.

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! Example 76 j
4- (2'-fluoro-4-biphenyly1) -2-pentanol

; To a solution of 8.97 g (0.035 mol) 4- (2 · -fluoro-4-biphenyIyI) -; 2-pentanone in 50 ml of dry benzene is added within 2
■ Minutes 6.07 g (0.021 mol) of a 70 percent. Solution of sodium-bis-

(2-methoxy-ethoxy) -dihydroaluminate in benzene, with one from the outside ; cools with ice. The mixture is then stirred for 1 hour at room temperature, decomposed with 10 percent. Hydrochloric acid, separates the layers and

wash the aqueous phase with 2 × 20 ml ether. The United

organic solutions are dried and evaporated in vacuo, the residue is purified by column chromatography on silica gel and
: finally distilled in a Pein vacuum. The colorless, viscous oil consisting of a mixture of the two possible diastereomers
■ boils at bp. _{Q Q & mmH} 121 - 126 ° C. The yield is 6.15 g

(68 % i )

_{mmH 121-126} ° (68 % of theory ).

The same compound is obtained in the same yield if the order of adding 4- (2'-fluoro-4-biphenylyl) -, 2-pentanone and sodium bis (2-methoxyethoxy) dihydroaluminate interchanged will.

Example 77

^; 4- (2'-fluoro-4-biphenyIy1) -2-butanol

, 12.0 g (0.05 mol) of (E) -4- (2 ^f -fluoro-4-biphenylyl) -3-buten-2-one, dissolved in 200 ml of ethanol, are in the presence of 5 g of copper-chromium oxide hydrogenated at 175 ° C. and 150 atm. hydrogen pressure until the hydrogen uptake ceases, which takes about 20 minutes
!are. After cooling, the catalyst is filtered off
■ The filtrate was concentrated, the residue on silica gel using initially benzene, later benzene / methylene chloride (volume ratio
, 1: 1) diromatographed to elute the product obtained
! Finally, twice more from petroleum ether using

! Recrystallized activated carbon. The product you are looking for is obtained in
• Form of colorless crystals with a melting point of 59-6O ⁰ C and in one

509828/103 7

Yield of 10.5 g (86 % of theory).

Example 78

4- (2'-fluoro-4-biphenylyl) -2-butanol

12.0 g (0.05 mol) of (E) -4- (2'-fluoro-4-biphenylyl) -3-buten-2-one, dissolved in 200 ml of ethanol, are added in the presence of 2 g of Raney nickel hydrogenated at 3 at pressure and 145 ° C. until 0.1 mol of hydrogen is absorbed. After cooling, the catalyst is filtered off, the piltrate is concentrated, the residue is carefully chromatographed on silica gel to separate off by-products, and the crude product thus obtained is recrystallized again from petroleum ether. The yield of colorless crystals with a melting point of 59 to 60 ° C. is 5.1 g (42 % of theory).

Example 79

4- (2-fluoro-4-biphenylyl) -2-butanol

24.03 g (0.1 mol) (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-one, dissolved in 150 ml 96 percent. Ethanol, are hydrogenated at room temperature and normal pressure in the presence of 10 g of Raney nickel. After about 0.1 mole of hydrogen has been absorbed, after about 20 minutes, the rate of hydrogen uptake drops sharply. After adding 0.5 ml of 40 percent Sodium hydroxide solution, the hydrogen uptake is faster again, the hydrogenation is ended after a total of about 90 minutes. The solution freed from the catalyst is neutralized with acetic acid and evaporated, the residue is mixed with 50 ml of water and extracted with ether to exhaustion. The ether extracts give 19.2 g (79 % of theory) of the compound formulated above in the form of colorless crystals with a melting point of 40 to 42 ° C. (gasoline).

Example 80 4- (2-fluoro-4-biphenylyl) -2-butanol

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12.0 g (0.05 mol) (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-one, dissolved in 100 ml 96 percent. Ethanol, are hydrogenated at room temperature and ₍ -3 at pressure in the presence of O ₃ I g of platinum dioxide and 1 ml of an O ₃ I: m iron (II) sulfate solution until the uptake of hydrogen has ceased, which takes about 5 hours The catalyst is filtered off, the filtrate is evaporated, the residue is partitioned between water and ether Melting point: 40 to 42 ° C. The yield is 10.1 g (83 % of theory).

Example 81

4- (2'-fluoro-4-biphenyIyI) -2-butanol

29.1 S (0.12 mol) 4- (2'-fluoro-4-biphenylyl) -2-butanone, dissolved in 200 ml ^ ethanol, are mixed with 1 g. platinized activated carbon, and 3 ml of a 10 percent. aqueous hexachloroplatinum (IV) acid solution and shaken for 4 hours at normal pressure in a hydrogen atmosphere. After the uptake of hydrogen has ended, the catalyst is removed, the filtrate is evaporated, the residue is chromatographed on silica gel and the product obtained is then recrystallized twice from petroleum ether. Melting point: 59 to 60 ^° C. The yield is 24.5 g (84 % of theory).

! Example 82

1 4- (2'-fluoro-4-biphenyly1) -2-pentanone

[A solution of 33.58 g (0.13 mol) 4- (2 ^! -Fluoro-4-biphenylyI) -l2-pentanol (mixture of the two diastereomers) in 500 is added dropwise with vigorous stirring and external cooling with ice ml of benzene

a solution of 68.6 g (0.23 mol) of sodium dichromate dihydrate in a mixture of 50 ml of glacial acetic acid, 90 ml of concentrated sulfuric acid: and 300 ml of water. Subsequently, a further 24 hours under Einhai-: tung a temperature 25-30 ⁰ C stirred.

509828/1 037

I. " ^61j " 2382583

! The benzene layer is separated, twice with 100 ml of water each time, Washed once with 200 ml of saturated soda solution and again with 100 ml of water, clarified with activated charcoal, and dried over sodium sulfate and evaporated. The remaining residue is chromatographed on Kie-'selgel using benzene for the elution, The product obtained is then recrystallized from gasoline.

The yield is 21.7 g (65 % of theory). Melting point ": 61

up to 62 ° C.

' Example 83

^: 4- (2-fluoro-4-biphenylyl) -2-pentanone

A mixture of 3 * 1.0 g (0.3 ¹ mol) of finely powdered chromium (VI) oxide and 500 ml of glacial acetic acid is heated on the steam bath while stirring vigorously and slowly mixed with a solution of 25.83 g (0 , 1 mol) 4- (2-fluoro-4-biphenylyl) -2-pentanol (melting point: 53 to 5 ¹ I ⁰ C) in 100 ml of glacial acetic acid. After 15 minutes, the mixture is allowed to cool, stirred into 2 l of ice water and extracted exhaustively with ether. The combined ether extracts are washed with water, saturated sodium hydrogen carbonate solution and again with water, treated with activated charcoal and sodium sulphate and evaporated. The remaining residue is carefully chromatographed on silica gel using benzene for elution to remove byproducts and starting material, and finally recrystallized from diisopropyl ether and cyclohexane. The colorless crystals with a melting point of 85 to 86 ^° C. are obtained in a yield of 10.8 g! % of theory). ■

Example 84

4- (2'-fluoro-4-biphenyIyI) -2-butanone

With vigorous stirring and external cooling with ice, add 70; ml of anhydrous pyridine 6.2 g (0.062 mol) chromium (VI) oxide, 15 minutes later a solution of 4.89 g (0.02 mol) 4- (2'- j) all at once Fluorine-4-biphenylyl) -2-butanol in 10 ml of dry pyridine, leaves!

509828/1037

; 30 minutes at 0 to 5 ° C, then 1 hours at room temperature. The mixture is then stirred into 300 ml of ice water, extracted exhaustively with ether, the combined ether extracts are washed • twice with water, once with 1 percent. Hydrochloric acid, again with water, then with saturated sodium hydrogen carbonate solution and again with water, dry it with sodium sulfate and evaporate it. 'The residue is chromatographed on silica gel using benzene for the elution, and the main product obtained is finally' distilled in a vacuum. Ma.n receives the sought-after 4 = (2'-fluoro-4-biphenylyl) -2-butanone with bp _Q ^ 151 to 154 ⁰ C and melting point; 30 ° C (petroleum ether) in a yield of 3.25 g ( 67 % of theory).

Example 85 (E) -4- (2-Fluoro-4-biphenylyl) -3-buten-2-one

; 24.2 g (0.1 mol) (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol are dissolved in 100 ml acetone and kept at a reaction temperature of 5 to 10 ° C dropwise with a solution of 10.0 g (0.1 mol) of chromium (VI) oxide in 35 ml of 35 percent strength. aqueous sulfuric acid added. The mixture is left to stir for 5 hours, diluted with 500 ml of ice water, extracted exhaustively with ether and worked up as in Example 83; To yield the pale yellow (E) -4- (2-fluoro-4-biphenylyl) -3-butene; 2-one van melting point of 82-83 ⁰ C (Diisopropylather) in a yield of 17.5 g (73% of Theory).
ϊ

Example 86 4- (2-fluoro-4-biphenylyl) -2-butanone

With ice cooling, 75.0 g (0.75 mol) of chromium (VI) oxide are added to 139.0 g (1.88 mol) of tert-butanol, the reaction mixture is diluted with 750 ml of benzene and the benzene solution obtained is dried of di-tert.-; j-butyl-chromate over anhydrous sodium sulfate. This oxidation ^; The mixture is stirred into a solution of 61.1 ig (0.25 mol) 4- (2-fluoro-4-biphenylyl) -2-butanol in 100 ml of dry benzene in the course of 30 minutes, the internal temperature being 5 to 6 ⁰ C is held. ■

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The mixture is then stirred for 48 hours at 35 ^° C., an aqueous solution of 126 g (1.0 mol) of oxalic acid dihydrate is added for hydrolysis of excess reagent, the layers are separated and the aqueous phase is drawn two more times with 200 each time ml of benzene. The combined benzene phases are washed with water, saturated sodium hydrogen carbonate solution and again water, dried over sodium sulfate and evaporated. The residue is purified on silica gel using benzene for the elution and then recrystallized twice from gasoline. The desired 4- (2-fluoro-4-biphenylyl) -2-butanone with a melting point of 41 to 42 ° C. is obtained in a yield of 22.4 g (37 % of theory).

Example 87 4- (2-fluoro-4-biphenylyl) -2-butanone

110 mg (0.45 mol) of 4- (2-fluorine-4-biphenylyl) -2-butanol are dissolved in 15 ml of dimethylformamide and treated with 166 mg (1.66 mol) of chromium (VI) oxide, whereupon 3 drops of concentrated sulfuric acid are added. With occasional swirling, the mixture is left to stand for 15 hours at room temperature, 100 ml of ethyl acetate are added and the mixture is carefully shaken with 100 ml of 10 percent strength using tap water while cooling from the outside. Sodium hydrogen sulfite solution. The phases are separated and the aqueous layer is extracted three times with 50 ml of ethyl acetate each time. The combined ethyl acetate phases are then washed once each with acidified sodium hydrogen sulfite solution, 1 η sodium hydrogen carbonate solution and water and, after drying with sodium sulfate, evaporated in vacuo, finally at 80 ° C., the dimethylformamide also being completely removed. The residue is chromatographed on 10 g of Kesel gel using benzene for the elution, and the main product is then recrystallized from gasoline. The desired 4- (2-fluoro-4-biphenylyl) -2-butanone with a melting point of 41 to 42 ^° C. is obtained in a yield of 80.7 mg (74 % of theory).

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' Example 88

'(E) -4- (2 ^t -Pluor-4-biphenylyl) -3-buten-2-one

; 4.07 g (0.0168 mol) of (Ε) -4- (2 · -fluoro-4-biphenylyl) -3-buten-2-ol are dissolved in 60 ml of ether, whereupon 20 ml of water are added. To: the well-stirred mixture is added under a nitrogen atmosphere

5.25 ml of 8 η aqueous chromic acid solution were added dropwise over a period of 30 minutes, followed by stirring for a further 16 hours at room temperature. The layers are separated, the aqueous phase is exhaustively extracted with ether, the ether phases are combined, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized twice from diisopropyl ether and a mixture of ethyl acetate and diisopropyl ether (volume ratio 1: 1) using activated charcoal. The pale yellow crisis stalle melt b.ei 113 - 114 ⁰ C. The yield is 2.46 g of X & l% of theory).

Example 89 \ (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-one

32.4 g (about 0.37 mole) of manganese (II) sulfate and potassium permanganate Freshly prepared manganese (IV) oxide are suspended in 200 ml of toluene and with stirring on the water separator until the water is completely drained heated. 21.8 g (0.09 mol) of (E) -4-j (2-fluoro-4-biphenylyl) -3-buten-2-ol are then added and boils under reflux overnight, after which the water separation ends and, according to the thin-layer

Ichromatogramm no more starting material can be detected. One filidamp the combined filtrates in a vacuum. Crystallized the residue one twice from diisopropyl ether using activated charcoal.

Melting point: 82-83 ⁰ C

Yield: 16.0 g (74 % of theory). _;

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! Example 90
s 4- (2-fluoro-4-biphenylyl) -2-butanone

; To a mixture of 65.0 g (0.60 mol) 1,4-benzoquinone, 14.8 g (0.06 mol) aluminum tert-butoxide and 1 l of anhydrous toluene are added: 31.03 while stirring g (0.127 mole) 4- (2-fluoro-4-biphenylyl) -2-; ; butanol. The mixture is left to stand at room temperature for 8 days with occasional stirring, then 5 ml of water are carefully added and the aluminum hydroxide formed is removed by filtration. The remaining toluene solution is washed successively with 500 ml of 5 percent strength each. Caustic soda and water, dry them over sodium sulfate and evaporate them in a vacuum. The residue is recrystallized twice from gasoline. The colorless crystals melt at 41 to 42 ^° C. The yield is 21.85 g (71 % of theory).

ι ^ä

Example 91 ι

j!

' (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-one

24.23 g (0.1 mol) (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol and 15 »81 g (0.1 mol) 2,3-dichloro 5,6-dicyano-1,4-benzoquinone are dissolved in 200 ml of anhydrous dioxane and stirred for 72 hours at room temperature. After adding 20 g of activated charcoal, the mixture is filtered, the filtrate is freed from the solvent, the residue is chromatographically purified on silica gel using benzene for elution. That; product thus obtained is recrystallized from Diisopropylather, j after which it melts at 82-83 ⁰ C. The yield is 21.1 gj (88 % of theory).

Example 92 !

4- (4-BiphenyIy1) -2-pent anon

15.1 g (0.0486 mol) of 2-Acety1-3- (4-biphenyIyI) butyric acid ethyl ester are stirred with 60 ml (about 0.075 mol) of 5 percent sodium hydroxide solution and 200 ml of ethanol for 19 hours at room temperature, the

509828/103 7

j - 69 - 23S2583

! Ester is saponified and the acid is already partially decarboxylated.

To complete the elimination of carbon dioxide to cook more 'S hours under reflux, the ethanol is distilled off, then cooled and extracted with ether from multiple times. The combined ether extracts are washed with water, dried over magnesium sulfate and evaporated; Finally the residue is recrystallized from petrol (bp. βθ to 8O ⁰ C). 10.0 g (86 % of theory) of the sought-after (ij-biphenylyl) -2-pentanone with a melting point of 59 to 60 ° C. are obtained.

Example 93 4- (2-fluoro-4-biphenylyl) -2-pentanone

Prepared analogously to Example 92 from ethyl 2-acetyl-3- (2-fluoro-4-biphenylyl) -butyrate in a yield of 19 % of theory. The colorless crystals melt after recrystallization from petroleum ether at 85 to 86 ° C.

example 3h

Prepared analogously to Example 92 from 2-acetyl-3- ^(2'-chloro-i i-biphenylyl) -buttersäureäthylester in a yield of 81% of theory. The colorless oil boils at _{bp.Q Qlt} - U ₁₁₁₁₁ Ip- ¹² O to 130 ⁰ C.

Example 95 4- (2'-Fluoro-4-biphenylyl) -2-pentanone

.32.84 g (0.1 mol) of 2-acetyl-3- (2'-fluoro-4-biphenylyl) butyric acid ethyl ester are with 200 ml of 20 percent. Hydrochloric acid and 200 ml of ethanol are refluxed until a sample is removed, which can be obtained by adding is brought to about pPI 2 to 3 by dilute sodium hydroxide solution, no more positive iron (III) chloride reaction to ß-ketoester shows (6 to 8 hours). The ethanol is distilled off, allowed to cool, etherified several times, the combined ether extracts are washed with water, saturated sodium hydrogen carbonate solution and again

509828/1037

with water and dry over sodium sulfate. The after Abdestillie- 'ren the solvent residue remaining melt after two recrystallisations from petrol at 60 to 61 ⁰ C. The yield is 19.5 g (76% dsr theory).

Example 96 ⁱ t ~ (2-Pluor- ¹ l-biphenylyl) -2-pentanone

3.56 g (0.01 mol) of 2-acetyl-3- (2-fluoro-4-biphenylyl) -butyric acid tert-butyl ester, prepared from l-bromo-l- (2-fluoro-4-biphenylyl) -ethane and Acetoacetic acid tert-butyl ester in the presence of potassium tert-butylate are heated to 150 ° C in an oil bath. After adding 0.1 g of p-toluenesulfonic acid, vigorous evolution of gas begins. To end the decomposition, the mixture is ^{heated to 200 °} C. for a further 60 minutes. It is allowed to cool and the ether solution is washed with water, saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated, and the residue that remains is recrystallized from diisopropyl ether and petroleum ether. 1.77 g (69 % of theory) of colorless crystals with a melting point of 85 to 86 ^° C. are obtained.

Example 97 ^ - (2-Fluoro-4-biphenylyl) -2-pentanone

A mixture of 3.56 g (0.01 mol) of 2-acetyl-3- (2-fluoro-4-biphenyIyI) -butyric acid tert-butyl ester, 20 ml of conc. Hydrochloric acid and ■ 20 ml of dioxane are refluxed for 5 hours. It is allowed to cool, diluted with 100 ml of water and extracted exhaustively with ether. The combined ether extracts are washed with water, saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated, and the remaining residue is recrystallized twice from petroleum ether. 1.86 g ^: (73 % of theory) of colorless crystals with a melting point of 85 are obtained

^; up to 86 ⁰ C.

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Example 98 ■ 4- (2-fluoro-4-biphenylyl) -2-pentanone

A mixture of 32.84 g (0.1 mol) of 2-acetyl-3- (2-fluoro-4-biphenylyl) butyric acid ethyl ester, 6.43 g (0.11 mol), is heated with stirring. Sodium chloride and 5.4 ml (0.3 mol) of water in 50 ml of dimethylsulfoxide for 5 hours at 150 ⁰ C. After cooling, the reaction is stirred Imischung in 200 'mL of water and takes the separated oil in _Äther_auf _.__ JPress is JLtherlösung washed with water, dried over sodium sulfate and evaporated. The residue that remains, 4- (2-fluoro-4-biphenylyl) -2-pentanone, melts after recrystallization twice from diisopropyl ether at 85 to 86 ^° C. The yield is 8.7 g (34 % of theory).

509828/1037

The new compounds of general formula I can be used for pharmaceutical purposes, if appropriate in combination with others Active substances of the general formula I, in the usual incorporate pharmaceutical preparation forms. The single dose is 25 to 400 mg, preferably 50 to 300 mg, the daily dose is 100 to 1000 mg, preferably 150 to 600 mg.

The following examples describe the production of some pharmaceutical preparation forms:

i Example I Tablets with 50 mg (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol

!composition:
1 tablet contains

Active substance 50.0 mg

Corn starch 247.0 mg

Polyvinylpyrrolidone 10.0 mg

Magnesium stearate 3.0 mg

310.0 mg i manufacturing process;

The mixture of the active ingredient with corn starch is with a; 14 # solution of polyvinylpyrrolidone in water through sieve 1.5 mm granulated, dried at 45 ° C. and rubbed through the above sieve again. The granulate thus obtained is mixed with rat Magnesiumstea- I and compressed into tablets.

Tablet weight: 310 mg
! Stamp: 10 mm, flat

509828/1037

- 73 - 2362583

Example II Dragees with 100 mg Q5) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol

[ Composition:

1 dragee contains: ι
! Production method: 100.0 mg Active ingredient 170.0 mg Cornstarch 8.0 mg gelatin 18.0 mg Talk H ₁ O ^m S Magnesium stearate 300.0 mg

The mixture of the active substance with corn starch with an aqueous gelatin solution '10 #igen granulated mm by 1.5 sieve, dried at 45 ⁰ C and rubbed 'again through the same screen. The granules obtained in this way are mixed with talc and magnesium stearate and pressed into tablet cores.
! Core weight: 300.0 mg
■ Stamp: 10 mm, convex

The tablet cores are coated with a casing using known methods ! which consists essentially of sugar and talc.

The finished coated tablets are polished with the help of beeswax. "Dragee weight: 58Ο mg.

Example III Gelatin capsules with 200 mg 4- (2-fluoro-4-biphenylyl) -2-butanol

'Composition:

509828/1 037

1 gelatin capsule contains:

j Active ingredient 200.0 mg

j corn starch 190.0 mg

\ Aerosil 6.0 mg

' Magnesium stearate 4.0 mg

'400.0 mg

ι Manufacturing process:

I The substances are mixed intensively and filled into size 1 gelatine capsules.
Capsule content: 400 mg

Example IV Suppositories with 200 mg 4- (2-fluoro-4-biphenylyl) -2-butanol

¹ composition:

: 1 suppository contains:

Active substance 200.0 mg

. Suppository mass (e.g. Witepsol W 45) 1 450 »0 mg

1,650.0 mg

Production method:

The finely powdered active substance is stirred into the suppository mass, which has melted and cooled to 40 ° C., using an immersion homogenizer. The mass is poured .for 38 ⁰ C in a slightly chilled molds.
Suppository weight: 1.65 g

509828/1037

Example V

Suspension with 200 mg 4- (2-fluoro-4-biphenylyl) -2-butanol

Composition:

Active ingredient dioctyl sodium sulfosuccinate (DONSS) Benzoic Acid Sodium Cyclamate Aerosil Polyvinylpyrrolidone Glycerin grapefruit flavor

Dist. Water ad

Production method:

4.0 ε 0.02 ε 0.1 G 0.2 G 1.0 ε 0.1 ε. 25.0 ε 0.1 ε 100.0 ml

In the heated to 70 ⁰ C water successively DONSS, benzoic acid, sodium and polyvinylpyrrolidone are dissolved. Glycerine and Aerosil are added, the mixture is cooled to room temperature and the finely powdered active substance is suspended with the aid of an immersion homogenizer. It is then flavored and made up to the given volume with water. 5 ml of suspension contain 200 mg of active substance.

Example VI

Dragees with 100 mg (E) -4- (2'-fluoro-4-biphenylyl) -5-penten-2-ol

Composition: '·

, i

Active substance 100.0 mg;

Milk sugar 55.0 mg j

Corn starch 42.0 mg '-

509 8 28/1037

2362583

I polyvinylpyrrolidone 2.0 mg j magnesium stearate I ₃ O mg

I 200.0 mg

Production method; i

! The mixture of the active ingredient with lactose and corn starch

; is with an oily aqueous solution of the polyvinylpyrrolidone '

Jdureh sieve 1.5 then granulated, dried at 45 ⁰ C and again;

• rubbed through a sieve 1.0 mm. The granules obtained in this way are treated with i

; Magnesium stearate mixed and pressed into tablet cores. \

Core weight: 200 mg;

■ 1

Punch: 8 mm, convex ^; The tablet cores obtained in this way are made by known processes

coated JMIT a shell consisting essentially of sugar and \ talc, the finished coated tablets are with the aid of ^bees:

polished wax. I.

Dragee weight: 290 mg _:

509828/1037

Claims (3)

Claims 1.) New general araliphatic ketones and carbinols Formula I, -C-CH ·. '■ .- .. ■ / ·. ■ ντ — γ } - / II in the R ₁ and Rp are hydrogen atoms or one of these two radicals one fluorine or chlorine atom and the other a hydrogen atom; R is a hydrogen atom, the methyl or ethyl group; * s ^ * f * H A is the group ^ C = O or -— · ^c \ QH Z ₁ and Zp are hydrogen atoms or, if m is zero adopts, together, an additional carbon-carbon bond; the symbol η the numbers 0,1,2 and m the numbers 2,4,6,8 or zero, provided that R ₁ or R “is a fluorine or chlorine atom and / or, R is the methyl or ethyl group and / or η the number 1 or 2 and / or A is the group "^ - ^ ^OH" mean. 2.) (E) -4- (2-fluoro-4-biphenylyl) -3-buten-2-ol 3.) 4- (2-Fluoro-4-biphenylyl) -2-butanol ' 4.) 8- (2'-Fluoro-4-biphenylyl) -2-octanol 5.) 6- (2 ^L -fluoro-4-biphenylyl) -2-hexanone 6.) 4- (4-Biphenylyl) -2-pentanone 7.) 8- (2 ^L -fluoro-4-biphenylyl) -2-octanone 8.) (E) -4- (4-biphenylyl) -3-penten-2-one 9.) (E) -4- (2'-Fluoro-4-biphenylyl) -3-penten-2-one .0.) 4- (2-Fluoro-4-biphenylyl) -2-pentanol .) (E) -4- (2'-Fluoro-4-biphenylyl) -3-penten-2-ol 5098 28/1037 2362509 12.) Process for the preparation of new araliphatic ketones and carbinols of the general formula I. R. CH (- I. I. ^Z 2 I. ^No. 1 > _ffl -A (-CH ₂ ) _n -CH ₃ I. in the R ₁ and Rp are hydrogen atoms or one of these two radicals is a fluorine or chlorine atom and the other is a hydrogen atom; R is a hydrogen atom, the methyl or ethyl group; A is the group ^ -C = O or ^ -C \ qh Z ₁ and Zp are hydrogen atoms or, if m assumes the meaning zero, together an additional carbon-carbon bond; the symbol η the numbers 0,1,2 and m the numbers 2,4,6,8 or zero, provided that R ^ or R «is a fluorine or chlorine atom and / or R is the methyl or ethyl group and / or η is the number 1 or 2 and / or A the group. -CC ^ gg represents, mean characterized in that a.) either metal organyls of the general formula II M (-CH ₂ J _n -CH ₃ II with compounds of the general formula III - C - CH (-CH ₉ ) - C - Y 509828/1037 or Organometallic organyls of the general formula IV C - with compounds of the general formula V, Y - (-CH ₂ ) _n -CH ₃ (V) be reacted at temperatures between -8O ⁰ C and + 10O ⁰ C in the presence of a solvent, where in the general formulas II, III, IV and V the symbols R, R ₁ , Rp, Z ₁ , Zp ₄ m and η are the initially have the meanings mentioned, X is an oxygen atom, provided that Y is a hydrogen atom or an NH _? Group, or represents a nitrogen atom, provided that Y assumes the meaning of an additional bond between the carbon atom and X, and M denotes a lithium atom or the residue Mg Hai, in which Hai is a chlorine, bromine or iodine atom, or b.) for the preparation of compounds of the general formula I in which Z ₁ and Zp denote hydrogen atoms, compounds ■ of the general formula I in which Z ₁ and Zp together denote an ₍ additional carbon-carbon bond, either with catalytically activated hydrogen, or, if in the starting compound of the general formula IA the: group ^ C = O, also hydrogenated with nascent hydrogen, by cathodic reduction or with a titanium (III) halide or ': 509828/1037 c.) for the preparation of compounds of the general formula I in which A represents the group ^ " ^c \ oh, compounds of the general formula I in which A is the group ^ - C = 0, by means of complex hydrides in a solvent at temperatures between -80 ° C and +100 ⁰ C, or with primary or secondary alcohols in the presence of; alcoholates of metals of the 1st to 3rd main group of the periodic table, or by the action of base; metals .in an alkaline medium in the presence of a hydroxyl-containing or aqueous organic solvent at temperatures between room temperature and the boiling point of the solvent, or by catalytic \ hydrogenation in a solvent at temperatures between 20 and 25O ⁰ C or by the action of thiourea-S, S-dioxide in aqueous-alcoholic solution in the presence of caustic alkalis at temperatures up to the boiling point of the \ solvent, or d.) for the preparation of compounds of the general formula I in which A is the group ^ C = 0, compounds of the general formula I in which A is the group ^ ^c \ qh, with chromium (VI) compounds at temperatures between 0 ° and 100 ⁰ C or with manganese (IV) oxide in the presence of a solvent at temperatures between 0 ° and 100 ⁰ C or with ketones in the presence of alcoholates of metals of the 1st to 3rd main group of the periodic table at temperatures up to the boiling point of the reaction mixture or with anhydrous dialkyl sulfoxides or alkylene sulfoxides in the presence of activators and acidic agents or with 2,3-dichloro-5,6-dicyan-1, dibenzoquinone in inert solvents at temperatures between 10 ⁰ C and the boiling point of the solvent , be oxidized or e.) for the preparation of compounds of the general formula I, in which A is the group ^ -C = 0, ß-ketoesters of 509828/1037 general formulas VI and VII, R COOR _C .11- - c - c - = / V = / II VI -CH " COOR VII in which the symbols R, R ₁ , R ₂ , Z ₁ , Z ₂ and η have the meanings defined at the beginning, m can assume the values 2,4,6,8 and R ₁ - an alkyl, cycloalkyl, aryl or aralkyl radical means, are saponified and decarboxylated or f.) for the preparation of compounds of general formula I, in which R is a hydrogen atom, Z. and Zp together are a carbon-carbon bond, A is the group ^ C = 0 and m assumes the value zero, either aldehydes of the general formula VIII, - C VIII R ₂ 509828/1037 in which the leftovers R ₁ and R _{2 have} the meanings given above, with ketones of the general formula IX, Ii ix H ₃ C - C (-CH) - in which η can assume the values mentioned at the outset, in the presence of basic catalysts at temperatures between -10 ⁰ C and +50 ⁰ C or in the presence of zinc oxide at temperatures between 150 and 200 ⁰ C under an inert gas of 10 to 300 atm pressure or, if the compound of the general formula IX is acetone, also in the presence of acidic agents or Aldehydes of the general formula VIII with triphenylphosphine acylmethylenes of the general formula X, CH-C- (CH ₂ ) _n -CK. in which η can assume the values mentioned at the outset, can be ^{reacted at temperatures between 50 and 120 °} C. or G. ) for the preparation of compounds of the general formula I in which Z ₁ and Z _? together a carbon-carbon bond and A is the group C = 0, m assumes the value zero and the remaining radicals have the meaning defined at the beginning 509828/1 037 have services, aldehydes of the general formula VIII or ketones of the general formula XI, - C «= ■ 0 in which R is a methyl or ethyl group, with crotonic acid esters of the general formula XII - 0, H ₃ C XII in which the radicals R ₁ and R 1., which can be the same or different from one another, denote alkyl radicals with 1 to 4 carbon atoms, cycloalkyl radicals with 5 to 7 carbon atoms, aryl or aralkyl radicals with at most 10 carbon atoms, with the exclusion of water in the presence of stronger Bases and dipolar aprotic solvents or in the presence of alkali metal amides condensed and the resulting intermediates of the general formula XIII OR, - C - CH - C - CH - COOH XIII are then saponified and decarboxylated or 5098 2 87 1037 OJi h.) for the preparation of compounds of the general formula I, in which Z. and Z are hydrogen atoms and A is the group ^ C =, mixtures of carboxylic acids of the general formulas XIV and XV, H-CH ₂ - (CH ₂ ) _m -C0 ₂ H XIV HO ₂ C- (CH ₂ ) _n -CH ₃ XV ; in which the symbols R, R ^, R «, m and η are those specified at the beginning Have meanings, are thermally decarboxylated and the reaction mixtures obtained in this way desired connections by physical separation processes to be isolated. 13.) The method according to claim 12a, characterized in that for the preparation of compounds of the general formula I in which A represents the group ^ -C = O, compounds of the general Formulas III and V, in which the remainder X Ο IJ Π - C - Y the group - C - NH ₂ or the cyano group means, are reacted with compounds of the general formulas II or IV. 14.) Method according to claim 12a), characterized in that 509828/1037 for the preparation of compounds of general formula I in which A is the group ^ ^c \ i ^OH compounds of the general formulas III or V, in which the radical - C - Y means the group - CH = 0, with compounds of general formulas II and IV are implemented, the metal organyls in excess or at least stoichiometric Proportions are used « 15.) Method according to claim 12a), characterized in that the aldehydes corresponding to the general formulas III and V are used in excess, after the hydrolysis of the : Reaction mixture a mixture of ketones and alcohols of the general formula I arises. 16.) Process according to claim 12a and 15, characterized in that ■ that the mixture obtained according to claim 15 of ketones and j alcohols of the general formula I to a uniform end product of the general formula I in which A is the group ^. C -. ^ ₁ TT is reduced. ; 17.) Process according to claim 12a and 15, characterized in that the mixture obtained according to claim 15 of ketones and ' alcohols of general formula I to a uniform end product of general formula I in which A is the group ^ C =: is oxidized will. 18.) Process according to claim 12a, 13, 14 and 15, characterized in that the solvent used is diethyl ether ₅ tetrahydrofuran, j 1,4-dioxane, ethylene glycol dimethyl ether, anisole, mixtures of; Ethers with aromatic hydrocarbons, aliphatic: hydrocarbons or methylene chloride is used. 19- j) method B according to claim 12, characterized _s that the catalytic hydrogenation in the presence of Raney cobalt, Raney Niekel, palladium on charcoal, palladium on barium sulfate, · j platinum or platinum (IV) oxide until the uptake of 1 to 1.2 509828/1037 Mol of hydrogen in the presence of a lower aliphatic alcohol, an aromatic hydrocarbon, ether or 'ester of a lower aliphatic carboxylic acid or in mixtures of these substances is carried out as a solvent at temperatures between 0 ° and ¹ JO ⁰ C and at a pressure of 0 to 100 at. 20.) Process according to claim 12 b and 19, characterized in that the catalytic reduction of compounds of the general formula I in which Z ₁ and Zp together represent an additional carbon-carbon bond and A is the group ^ -C = O, the resulting carbinols and ketones of the general formula I, in which Z. and Zp are hydrogen atoms, are then oxidized to a uniform end product of the formula I in which A is the group ^ C = O. 21.) The method according to claim 12 b and 19, characterized in that in the catalytic reduction of compounds of the general formula I, in which Z. and Z "together denote an additional carbon-carbon bond and A is the group ~ P Cd ^ oH i s ^st resulting carbinols and ketones of the general formula I in which Z ₁ and Z ₂ are hydrogen atoms, then at a uniform final product of formula I in which a is the group ^ - ^ ^{c ::} .0H ^ ^st 'be reduced. 22.) Process according to claim 12 b and 19 for the preparation of compounds of general formula I in which A is the group ^ C = O and Z. and Zp denote water st off atoms, characterized in that a compound of general formula I. , in which Z ₁ and Z _? together form a carbon-carbon bond and A represents the group ^ C = O, hydrogenated in the presence of colloidal nickel boride. 23.) The method according to claim 12 b, characterized in that the saturation of the olefinic double bond by nascent Hydrogen using sodium amalgam in an acidic medium, using zinc amalgam in aqueous alcohol-acetic acid mixtures 509828/1037 I - 87 - or by means of electrolysis in a neutral or acidic medium I follows. j24 _o ) Method according to claim 12 b _s characterized in j that ^: j titanium (III) chloride is used as titanium (III) halide and ^; i is performed, the reduction in an aqueous-ethanolic ammonia solution I at temperatures up to 100 ⁰ C. J25.) Process according to claim 12 C _9, characterized in that as complex hydrides alkali or alkaline earth aluminum hydrides, alkoxy alümlniümhydride, alkali and alkaline earth borohydrides, cyano and alkoxy borohydrides, combinations of lithium aluminum hydride or sodium borohydride with aluminum chloride or boron trifluoride j or diborane are used the reduction in an ether, j aromatic hydrocarbon or in mixtures of these substances ι as a solvent, reductions with sodium borohydride, sodium S cyanoborohydride and sodium trimethoxyborohydride also in alcohol 1 len can be carried out as a solvent. ; 26.) Process according to claim 12c _s characterized in that the \ reduction with isopropenol is carried out in the presence of aluminum isopropylate, magnesium isopropylate, sodium ethylate or aluminum dichloro isopropylate in the presence of an aromatic hydrocarbon as solvent at temperatures up to the boiling point of the solvent. 27 ·) Process according to claim 12 c, characterized in that sodium, sodium amalgam, calcium, magnesium, zinc, zinc amalgam, aluminum or aluminum amalgam, alcohols, moist ether, moist benzene are used as solvents, such compounds of the general formula I arise,. in which Z ₁ and Z_ have the meaning of a hydrogen atom. 28.) The method according to claim 12 c and 27 _S, characterized in that i that sodium is used in liquid ammonia in the presence of ammonium chloride, such compounds of the general ·. my formula I arise in which Z * and Zp are hydrogen atoms 509828/1037 are. 29 ·) Process according to claim 12 c, characterized in that the catalytic hydrogenation with platinum, Raney nickel, palladium on animal charcoal, copper-barium-chromium oxide, ruthenium, rhodium on animal charcoal or copper chromite in alcohols, mixtures of water and alcohols, ethers , ^{Essigsäureestern:} or aliphatic carboxylic acids as solvents, with the use of metal catalysts at temperatures between 20 and 100 ⁰ C, with the use of oxidic catalysts at temperatures between 100 and 25O ° C, is carried out, such compounds of general formula I are formed, wherein Z _1: and Z _{2 are} hydrogen atoms and A is the group ^ ^C \ 0H 30.) The method according to claim 12 d, characterized in that as Chromium (VI) compounds sodium dichromate, potassium dichromate, Chromium (VI) oxide or di-tert-butyl chromate in water, glacial acetic acid, Acetone, petroleum ether, benzene, carbon tetrachloride, pyridine, dimethylformamide, dilute sulfuric acid or mixtures of these Solvent come to use or the oxidation with ^! Chromium (VI) oxide is carried out in dimethylformamide in the presence of concentrated sulfuric acid. j ^! j 31.) The method according to claim 12 d, characterized in that j I. ι Manganese (IV) oxide in the presence of petroleum ether, acetone, diethyl? i ether or tetrahydrofuran is used. 32.) Process according to claim 12 d, characterized in that the oxidation with ketones in the presence of aluminum alcohol-ι th is carried out using acetone, cyclohexanone or 1,4-benzoquinone and benzene or toluene as additional solvent. 33.) Process according to claim 12 d, characterized in that the dialkyl sulfoxide or alkylene sulfoxide is dimethyl sulfoxide or tetramethylene sulfoxide is used. 509828/1037 ! - 89 - 2362588 ■ 34.) Process according to claim 12 d and 33 »characterized in that as activators of the dialkyl or alkylene sulfoxides Ν, Ν'-dicyclohexylcarbodiimide Ν, Ν'-diisopropylcarbodiimide, N, N ^T - _: diethylcarbodiimide, N, N'-di - (p-tolyl) -carbodiimide _s N-Cyclo-: hexyl-N ^t -ZJ- (3-pyridyl) -l-ethyl7-carbodiimide, N-ethyl-5- 'phenyl-isoxazolium-3'-sulfonate, trichloroacetonitrile , Ethoxyacetylene or diphenylketene-p-tolylimine or inorganic or organic acid anhydrides such as acetic anhydride, benzoic anhydride, phosphorus pentoxide, polyphosphoric acid or pyridine antisulfuric acid can be used. 35 ·) Method according to claim 12 d, 33 and 3 ^ j characterized in that that as acidic agents anhydrous phosphoric acid, phosphorous acid, cyanoacetic acid, pyridinium phosphate, pyridinium sulfate, Dichloroacetic acid and pyridinium trifluoroacetate are used. 36.) Process according to claim 12 d, 33, 3 ^ and 35, characterized in that the reaction in the presence of with water is not miscible cosolvents such as benzene or ethyl acetate is carried out. 37.) The method according to claim 12 e, characterized in that the saponification is carried out in a weakly alkaline or acidic solution and the decarboxylation is catalytically accelerated by acids or bases. 38.) Process according to claim 12 e and 37 »characterized in that compounds of the general formulas VI and VII, in which Rc is a tertiary alkyl radical, are pyrolyzed in the presence of p- ■ toluenesulfonic acid, compounds of the general formula I being formed in where A is the group --C = O. ^; 39.) The method according to claim 12 e, characterized in that: esters of the general formulas VI and VII by heating with Alkali metal halides and pseudo halides or sodium; 6098-28 / 1Q3.7 phosphate in the presence of moist dimethyl sulfoxide or other dipolar aprotic solvents at temperatures between 1 * 10 and 185 ° C to give compounds of the general formula I, in which A is the group ^ C = 0, decarbalkoxylated. ¹ IO.) Process according to claim 12 f, characterized in that alcoholic or aqueous solutions of j alkali or alkaline earth metal hydroxides, aluminum alcoholates, piperi-r dinacetate or basic ion exchangers are used as * basic catalysts, since ketone in a 3- to 100 -fold molar excess is applied j and water or alcohols used as solvent I i will be. J 41.) The method according to claim 12 f, characterized in that j the implementation of a compound of the general formula VIII ι with one of the general formula X in ethereal i Solvents takes place. j 42.) Process according to claim 12 g, characterized in that the bases are alkali metal alcoholates in the presence of hexamethylphosphoric triamide or dimethylformamide are used. 43.) The method according to claim 12 g, characterized by the use of alkali metal amides in the presence of liquid Ammonia. 44.) The method of claim 12 g, 42 and 43 »characterized gekennzeich net that the intermediate of general formula Xil-X without isolation in the presence of concentrated hydrochloric acid is decarboxylated at 80 to 100 ⁰ C. 45.) The method according to claim 12 h, characterized in that thermal decarboxylation by dry distillation of a mixture of calcium or barium salts of acids of the general formulas XIV and XV. 509828/1037 • 46.) Method according to claim 12 h, characterized in that i_ the thermal decarboxylation of a mixture of acids; of the general formulas XIV and XV at temperatures between 300 and 480 ° C over catalysts of calcium, barium or; Thorium oxide or manganese (II) oxide is carried out on pumice stone, a ketone of the general formula I being obtained directly, ί in which Z. and Zp are hydrogen atoms and A is the group ^ G s 0. 47.) Method according to claim 12 h, characterized by the pyro * lysis of carboxylic acids of general formula XIV with alkali salts of carboxylic acids of general formula XV and anhydrides the acids of the general formula XV. 48.) The method according to claim 12 h _s 45, 46 and 47, characterized in that the desired compounds of general formula I, in which A represents the group ^> C = 0, by fractional distillation, fractional crystallization, from the resulting ketone mixtures or isolated by chromatographic methods. 49.) Medicines, characterized by a content of one or more compounds of the general formula I in addition to usual carriers and / or auxiliaries. 509828/1037