DE1493323A1 - 1,2-Diphenyl-3,4-dihydronaphthalenes and their acid addition salts and quaternary ammonium compounds - Google Patents

Description

U93323

DR. JU ^ DiPL-C'FM. WALTER BEIL

·. ·; -J WOLFF

¹ ■ S3 = December 1968

, v, ^; U- HIGHEST

Our no. 10 823

The Upjohn Company Kalamazoo (Mich., V.St, A.)

1,2-Diphenyl-3,4-dihydronaphthalenes and their acid addition salts as well as quaternary ammonium compounds

The invention relates to 1,2-diphenyl-3,4-dihydronaphthalenes the general formula

.OM

in which M is hydrogen or an alkali metal, R ^ and Rp a lower alkyl, lower alkenyl, lower alkoxy or lower alkenyloxy radical, the hydroxyl group, fluorine or chlorine, the 'i'rifluormetfoyl-, a lower alkyl mercapto radical or ie group -0- A-iJ ^ 3, where A is an Allcylenrest with '<d-6 carbon atoms, R, and R. individually low alkyl purity or together with the nitrogen atom a 5- to

909829/1572 bad original

Documents {Art 7 g 1 as. 2 rJr. I C ^ u 3 dos Alterunuaaee. v. 4,9.19S2I

7-membered saturated heterocyclic radical form and x and y represent the numbers 0.1 or 2, as well as pharmacologically suitable acid addition salts and quaternary ammonium derivatives of compounds in which M is hydrogen and

at least one of the radicals R ^ and Rp the group -0-Α ~ Ν (^ 3 means.

The inventive method for preparing these compounds is that they be beka _nn -fcer, a 1,2,3 '4-tetrahydro-2-phenyl-1-naphthalenone in a general

in the ^ c ^ ¹ ^ ^ 6 a lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or the 2-tetrahydropyranyloxy radical, fluorine or chlorine, the trifluoromethyl radical, a lower alkyl mercapto radical or the group

- 0 - A - N ■ * mean in the presence of an inert orga- ^R 4

Solvent with a Grignard reagent of the general formula

III

Mg shark

BATHROOM OPlGINAL

9/1572

converts, in which Hai represents a halogen atom, optionally formed carbinol is dehydrated, the obtained
Compound of the general formula

IV

acid hydrolyzed and, if necessary, then the
The compounds obtained are converted into alkali metal salts, acid addition salts or quaternary ammonium compounds.

The measures used according to the invention are known as such. For example, Grignardation is a cyclic one
Ketones are described in U.S. Patent 2,566,357.

By the term "lower alkyl" is meant alkyl
to be provided with 1 to 8 carbon atoms, such as the methyl, ethyl, i'rcpyl, butyl, amyl, hexyl, heptyl, octyl radical and their isomers; the expression "lower alkylene radicals" means alkenyl radicals having 2 to 8 carbon atoms, such as the vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl radical and their isomers; the expression "lower alkoxy_ _res te" alkoxy radicals having 1 to 8 carbon atoms, such as methoxy, ethoxy, rropoxy, butoxy_ amyloxy, hexyloxy, heptyloxy, cycloxy radical and their isomers; under the expression "lower alkenyloxy" alkenyloxy _res -te with 2. "to S carbon atoms, such as the Vinyloxv- Allyloxy-, Butenj'l-

BATH ORIGINAL
909829/1572

oxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy radicals and their isomers. The term "lower alkyl mercapto radicals" denotes alkyl mercapto radicals with 1 to 8 carbon atoms, such as the methyl mercapto, ethylgiercapto, propyl mercapto, butyl mercapto, amyl mercapto, hexyl mercapto, heptyl mercapto, octyl mercapto radical and their isomers; the term ^M alkylene groups with 2 to 6 carbon atoms "the ethylene, propylene, butylene, amylene, hexylene radical and their ^ somers. The 5- to 7-membered saturated heterocyclic ring formed from R, and R. and the adjacent nitrogen atom may be the pyrrolidine ring, substituted by lower alkyl groups pyrrolidine ring, such as the 2-methylpyrrolidin, 2,2-Dimethylpyrrolidin- or 3 Methylpyrrolidinring; the piperazine ring, by a lower alkyl group substituted Pipera in-ring _such as the 2-methylpiperazine, 4- Methylpiperazine or 2,4-dimethylpiperazine ring; the piperidine ring, a piperidine ring substituted by lower alkyl groups, such as the 2-methylpiperidine, 3-methylpiperidine or 4 »4-dimethylpiperidine ring; the morpholine, hexamethyleneimino, homopiperazine or homomorpholine ring

The compounds according to the invention can be present as free phenols or in the form of their alkali metal salts, for example as sodium, potassium or lithium salts, and also as acid addition or quaternary ammonium salts when M is hydrogen and R ₁ and / or R _{2 are} the group -OAN ^ 3 · represent · Suitable acid addition salts are mixed with pharmacologically acceptable acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, lactic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, acetic acid, propionic acid, maleic acid, malic acid, tartaric acid, citric acid, cyclohexylic acid and ascorbic acid. The quaternary ammonium

909829/1572 _BAD original

Salts are obtained by reacting the free phenols with quaternizing agents such as lower alkyl halides, bis (lower alkyl) sulfates, aralky! halides and lower Alkyl aryl sulfonates. Under the term "aralkyl" are To provide aralkyl groups with 7 to 13 carbon atoms, such as the benzyl, phenethyl, phenylpropyl and benzhydryl radicals The term "lower alkyl aryl sulfonates" denotes Esters of lower alkanols and arylsulfonic acids, such as benzenesulfonic acid, toluenesulfonic acid, xylene sulfonic acid and similar acids, examples of quaternary salts are methobromide, methojodide, ithobromide, propyl chloride, Butyl bromide, octyl bromide, methyl methosulphate, ethyl ethosulphate, Allyl chloride, allyl bromide, benzyl bromide, benzhydryl chloride, methyl ~ p-toluene sulphonate and ethyl p-toluene sulphonate.

The compounds according to the invention reduce fertility and in this respect are clearly superior to the 2,3-diphenylindenes described in "Society of Chemical Industry", pp. 2098/99, 1961. The investigation of the 1- (p-hydroxylphenyl) -2-phenyl-6-methoxy-3,4-dihydronaphthalene according to the method explained in "Proceedings of the Society for Experimental Biology and Medicine" S, 163-166 resulted in an MDE ₅₀ of 0.025 mg / kg / day. The MED ₅₀ of 2-phenyl-3- (p-diethylaminoethoxyphenyl) -6-methoxy-indene hydrochloride, ie the most effective of the known 2,3-diphenyl-indene derivatives, on the other hand, was ± 5 mg / kg / day. The compounds according to the invention are therefore 20 times as effective as the known indenes. Like these, they are not steroids and therefore do not have the undesirable side effects of these compounds.

The compounds according to the invention also have anti-inflammatory, antimicrobial and central nervous system stimulating effects,

mm Q mm

Due to their anti-inflammatory effect, they are suitable for topical use in cases of inflammation and burns, also for atopic treatment of dermatitis and contact dermatitis

For administration to humans and mammals can the compounds according to the invention with solid pharmaceutical carriers to form tablets, powders, capsules and the like Dosage forms are processed. With suitable solvents or dispersants, they result in liquid oral fluids and parenteral administration forms.

The compounds according to the invention are also valuable starting materials for further reactions. For example, the free phenols, when reacted with tertiary aminoalkyl halides of the formula Hal-AN ^/ _P 3 in the presence

^ 4 a base such as sodium hydroxide, potassium hydroxide or sodium methylate Aminoalkyl ethers, which also reduce fertility (see the publications by Lednicer et al., Chemistry and Industry, 1961, pp. 2098; ibid. 1963, p. 408).

In the inventive reaction that is carried out under anhydrous conditions, preferably in the presence of an inert solvent, such as dibutyl ether, diisopropyl ether or tetrahydrofuran, with the Grignard reagent is d _a s ketone (il) under conventional Grignardierungsbedingungen reacted (III). Tetrahydrofuran is the preferred solvent. The reaction can take place at temperatures between about ⁰ ° C. and the boiling point of the solvent used; it is preferred to work at elevated temperatures, for example at or near the boiling point of the reaction mixture.

The reaction time can depend on the reaction temperature used fluctuate greatly. If you work at elevated temperatures

6 0Ö829 / 1S7

ff · «
1 1 · · ·

U93323

temperatures, e.g. at the boiling point of the reaction mixture, bo are generally required several hours for a complete conversion.

The desired compound (i) can first be isolated as tetrahydropyranyl ether and the ether group can then be removed from it. However, it is also possible to split off the ether group during the isolation of the reaction product. Removal of the ether group is easily by hydrolysis with mineral acids achieve and is preferably carried out during the working up of the ^x roduktes.

For example, the reaction mixture obtained can be decomposed by adding water or ammonium chloride solution, whereupon separating the organic layer and removing the solvent. The residue from the ^ etrahydropyranyläther (IV) is then hydrolyzed, preferably by adding a solution of the ether in a suitable organic inert Solvents such as acetone, methanol, ethanol or mixtures of these solvents with water and an aqueous one Mineral acid, such as hydrochloric acid or hydrobromic acid, relocated and let stand.

The desired compound (i) is obtained from the hydrolysis mixture isolated in a known manner, e.g. by solvent extraction, and then, if necessary, purified in the usual way, e.g. by chromatography or recrystallization.

The compound (I) can by appreciable amounts of the corresponding Carbinols of the general formula

SAD OWGfNAL 909829/1 572

If such a mixture is obtained from the desired compound (I) and the corresponding carbinol (VI), this can be dehydrated in a manner known per se in order to obtain the compound (I) exclusively. The elimination of water can, in most cases by heating the carbinol in a solvent such as benzene or toluene, xylene, forming trope8 mixture with water an a _zeo, in the presence of traces of a strong acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid can be achieved . The water formed in the sserabspaltung W _a is removed azeotropically. A solution of the compound (I) from which it may be obtained by evaporation of the solvent or in other known ^ else obtained · sometimes requires the ^w asserabspaltung from the carbinol (V) severe conditions such as heating at a temperature in the or is close to the melting point of the compound, preferably in the presence of an inert gas, until the W _aS8e cleavage is complete.

If R .. and / or R ₂ in the starting ketone (II) are free hydroxyl groups, they must be protected from Grignardation by a group which can then be removed to form the compound (I) with free hydroxyl group or free hydroxyl groups. The conversion of the free hydroxy compound into the corresponding ethrahydropyranyl ether is particularly suitable. This transformation can

909829/1572

U93323

be made by the fact that the ketone having free hydroxyl groups in the presence of a trace of p-toluenesulfonic acid or a mineral acid such as hydrochloric acid or hydrobromic acid treated with 2,3-dihydropyran. The tetrahydropyranyl groups after the implementation according to the invention has been carried out together with those from the Grignard compound (ill) derived tetrahydropyramyl groups removed.

The Grignard reagents (III) are obtained in a manner known per se V / eise by reacting magnesium in an anhydrous inert solvent such as dibutyl ether or diisopropyl ether or tetrahydrofuran with the tetrahydropyranyl ether of the corresponding halophenol.

With the exception of those in which Rr and / or Rr is an alkenyloxy radical

si
or the group -0-AN _x - ^ mean, according to the following reaction

scheme can be obtained:

809829/167 2

VIII

XII

After the above reaction 8 chema is a correspondingly substituted Benzophenone (VI) with a suitably substituted benzaldehyde (VII) under customary conditions for corresponding chalcone (VIII) condensed, e.g. in the presence of a base such as sodium hydroxide or potassium hydroxide, in an inert solvent, such as a mixture of water and a lower alkanol, e.g. methanol or ethanol »

908829/1572

Usually one works at or below room temperature and, if necessary, cools from outside. The Chalcone (VIII) is isolated from the reaction mixture and purified in a known manner, e.g. by extraction and subsequent Distillation.

The chalcone (VIII) obtained in this way is then reacted with hydrocyanic acid, e.g. by treatment with an alkali metal cyanide, such as sodium cyanide or potassium cyanide in the presence of acetic acid and an inert solvent such as aqueous Methanol or aqueous ethanol (Newman, J. Am. Chem. Soc. Vol. 60, p. 2947, 1938) into the corresponding nitrile (IX) convicted. The nitrile (IX) generally precipitates as a solid and can be filtered off and recrystallized getting cleaned.

The nitrile thus obtained (IX) is then hydrolyzed in the usual else ^w to keto acid (X), for example, until the Hydrolyyse substantially completely by heating under reflux in the presence of an aqueous mineral acid such as sulfuric acid. The desired acid (X) is generally separated out as a pesticide and can be filtered off and purified by recrystallization or other measures, for example by conversion into an alkali metal salt and subsequent acidification with regeneration of the free acid.

The keto acid (X) thus obtained is then reduced to form the acid (XI). The reduction can be carried out in any way; amalgamated zinc is particularly suitable as a reducing agent. For the treatment of the keto acid (X) with zinc amalgam in the presence of a mineral acid ma _n receives the desired acid (XI) in excellent yield. The acid (XI) may be made of the reaction mixture in a conventional ^h else be isolated, for example by decanting

_; 909829/1572

of the liquid reaction mixtures, - solvent extraction the decanted liquid and removal of the solvent, The acid obtained in this way is generally sufficiently pure for further processing. If desired, can they are purified in a manner known per se, e.g. by distillation, recrystallization or conversion into a Alkali metal salt and subsequent acidification with formation the free acid.

In the last stage of the process according to the invention, the acid (XI) is eyclized to a-tetralone (XII) in the presence of a Lewis acid (see Fieser and Hershberg, loc. Cit.). Hydrogen fluoride is preferred as the Lewis acid. A particularly advantageous method for cyclizing the acid (XI) is that the latter is stirred in liquid hydrogen fluoride and can evaporate in the hydrogen fluoride at about 20-3O ⁰ C. The a-tetralone (XII) is then else isolated in the usual ^w of the residue, for example by dissolving the residue in a suitable solvent such as ether, washing the resulting solution with an aqueous solution of a base such as sodium carbonate or sodium hydroxide, and evaporation of the washed solution to dryness. The a-tetralone (XII) can, if desired, be further purified in a customary manner, for example by recrystallization.

The acid (XI) can also be converted into the corresponding Acid chloride and treatment of the acid chloride with aluminum chloride or tin chloride to give the tetraion (XII) cyclized (see Fieser and co-workers, J. Am. Chem. Soc, Vol. 60, p. 170, 1938).

a-tetralones, in which R, - and / or Rg are hydroxyl groups, is conveniently obtained by dealkylation of compounds of formula (XII), in which R ^ and / or R ^ alkoxy groups

9 0 9829/1572 bad OFlGiNAL

are. The dealkylation is carried out in the usual ^w else, for example by heating with aluminum chloride or bromide in the opposite waiting an inert solvent such as benzene or xylene.

α-Tetralones (XIl), in which Rr and / or Rg are alkenyloxy groups, can be obtained by alkenylation of compounds in which Rj and / or Rg are hydroxyl groups. The alkenylation can be carried out in a known else ^w, for example, by reacting the free hydroxyl compound with alkenyl halides in the presence of a base such as potassium carbonate or sodium methylate.

The a-tetralone _{R of} the formula XII, in which Rr and / or Rg the

Group -0 — AN ^ g can _{be represented} by etherification

4th
the free hydroxyl compound with one. Aminoalkyl halide obtained.

The enzophenones used as starting materials are obtained from appropriately substituted benzoic acids by conversion into acid chlorides and subsequent reaction with a diarylcadmium compound, Chemical Reviews, Vol. 40, p. 15, 1947.

The benzaldehydes (VII) are correspondingly substituted - ^ enzoylchloride by reduction with lithium tri-tert.-butoxylaluminum hydride available, see Brown et. al., J. Am. Chem. Soc., Vol. 80, pp. 5377, 1958.

The α-tetralons (XII) can also be according to Newman, J. Am. Chem. Soc, Vol. 62, p. 2295, 1940 by implementing a correspondingly substituted benzyl cyanide of the general formula

909829/1572

U93323

-H-

CH ₂ CN

with an appropriately substituted phenethyl bromide of the general formula

in the presence of sodium amide, hydrolysis of the nitrile obtained and cyclysation of the acid formed as above described.

The acid addition salts of the compounds according to the invention of the general formula (i), in which M is hydrogen and H ₁ and / or Rg is a tert. _{Amino group can be obtained by processes known per se. For example} , the free base can be reacted with a pharmacologically acceptable acid in the presence of an inert solvent such as water ether, lower alkanols such as methanol or ethanol.

The quaternary ammonium salts are obtained by reacting the free base with a quaternizing agent such as an alkyl halide such as methyl iodide, ethyl chloride or Isopropyl bromide, an alkenyl halide such as allyl chloride or allyl bromide, a dialkyl sulfate such as dimethyl sulfate or diethyl sulfate, an aralkyl halide such as benzhydryl chloride, ^ enzyl chloride or phenethyl bromide or an alkylarylsulfonate, such as methyl p-toluenesulfonate. The ümaetsuxig is preferably carried out with heating of the reactants in the presence of an inert solvent, such as aceto

909829/1572

nitrile, acetone, methanol or ethanol. In general the quaternary salt separates out of the solution when the reaction mixture cools and can pass through Filtration can be isolated. The purification can be carried out in the usual way, for example by recrystallization.

The anion of the quaternary ammonium salt obtained can be exchanged for any other anion, e.g. against an anion of one of the acids mentioned above, e.g. a quaternary ammonium salt, for example with Silver oxide, converted into the quaternary hydroxide and the hydroxide thus obtained react with the desired acid.

The following examples explain the invention Procedure.

Example 1 1- (p-hydroxy-phenyl) _-2-me thoxy phenyl_.6_ - ^, 4-dihydro-naphthalene.

A solution of 5.83 g of 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone in 75 ml of tetrahydrofuran was added to a tetrahydrofuran solution containing 0.0247 mol of a from magnesium and p-bromophenol tetrahydropyranyl ether prepared Grignard reagent. The received The mixture was refluxed for 16 hours cooled, mixed with 10 ml of water, filtered and the filtrate occurred diluted with ether. The organic layer was separated, washed well with water and dried over anhydrous Dried sodium sulfate. The dried solution was filtered and the piltrate was dried under reduced pressure evaporated. The residue was dissolved in 100 ml of tetrahydrofuran and treated again with the above Grignard reagent, The reaction mixture from the second Grignardation became processed as in the first pail. The obtained rubbery Substance was dissolved in 200 ml of benzene, i.e. 200 mg of p-toluene ~

BATH ORIGINAL

9 0 9 8 2 9/1572

sulfonic acid, and the mixture using a Dean-Stark water scavenger heated to reflux, until no more water was caught in the water catcher. The solvent became under reduced pressure distilled off and then the residue dissolved in a mixture of 200 ml of acetone and 70 ml of 0.5 η-hydrochloric acid. the The solution was left to stand for 2 hours at room temperature (about 25 ° C.) and then extracted with ether. The organic Layer was separated and made more aqueous with 5 pointers Extracted potassium hydroxide solution. The aqueous alkaline The extract was acidified with hydrochloric acid and the solid which separated out was filtered off and dried. He was in Dissolved methylene chloride and chromatographed over synthetic magnesium silicate. The column was filled with hexane hydrocarbons, containing increasing amounts of acetone, eluted; those fractions that are due to the infrared spectrum or paper chromatographic tests contained the desired compound, became Trolkene evaporated, - ^ he residue was twice from cyclohexane recrystallized. 0.71 g of 1- (p-hydroxyphenyl) -2-phenyl-6-methoxy-3,4-dihydro-naphthalene were obtained in the form of a crystalline solid from melting point 130 to 131.5 ° C.

Anal calcd for C ₂ -H ₂₀ O ₂ : C 84.12; H 6.14; found: C, 83.64; H 5.96.

Example 2 1- (p-Hydroxyphenyl) -2-phenyl-6- (2-diethylaminoethoxy) -3,4-dihydro-naphthalene and its hydrochloride

For the preparation of the starting material, 2-pnenyl-6- (2-diethylaminoethoxy) -1,2,3,4-tetrahydro-1-naphthalenone, was a suspension of 11.6 g of 2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-1-naphthalenone, from 2-phenyl-6-methoxy-1,2,3,4-

909829/1572

BAO

tetrahydro-1-naphthalenone with aluminum bromide in benzene (Journ. Chem. Soc. Vol. 82, p. 5205, 1960) treated in 200 ml of methanol with 10 ml of 4.8% sodium methylate solution. The mixture was stirred for 15 minutes and then 13.2 g of a 1ii- ^ emicches from 2-diethylaminoethyl chloride and toluene were added. The resulting mixture was refluxed for 17 hours and then the solvent was ^{removed under reduced 1} WcIc. The residue was treated with a mixture of ^rt ater and methylene chloride, the organic layer separated, washed with ater ^rt and then washed with brine and evaporated to dryness. The residue was dissolved in 40 ml of ethanol and treated with 120 ml of saturated ethanolic picric acid. The pesticide which separated out was filtered off and recrystallized from acetonitrile. 13.15 g of 2-phenyl-6- (2-diethylaminoethoxy) -1,2,3,4-tetrahydro-1-naphthalenone were obtained in the form of the picrate; F = 180-184 ° C, an analytical sample was obtained from Schaelzpunkt 185-186 ⁰ G By further recrystallization from the same solvent.

Anal calculated for

found:

C 59.36; H 5.34; N 9.89; C 59.18; H 5.45; W 9.99.

A mixture of 7.46 g of the picrate, 50 ml of methylene chloride and 50 ml of about 14% ammonium hydroxide solution was shaken at room temperature for 2 hours. The organic layer was separated, washed once with aqueous ammonia, then with water, then with brine and evaporated to dryness. A solution of the residue in 50 ml of tetrahydrofuran was added to the Grignard reagent obtained from 7.70 g of the tetrahydropyranyl ether of p-bromophenol and 0.73 g of magnesium in 80 ml of tetrahydrofuran. The resulting mixture WUR <le 17 hours under reflux, then cooled and decomposed by careful addition of ^w ater.

BATH ORIGINAL

909829/1572

The resulting mixture was filtered and the filtrate with Ether diluted. The organic layer was separated, washed well with water and over anhydrous sodium sulfate dried. The dried solution was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of tetrahydrofuran and, as described above, again with the Rignard reagent treated. The reaction mixture from the second Grignardation was worked up as in the first i'all. The obtained gummy residue was dissolved in 150 ml of 2.5N hydrochloric acid suspended. The deposited solid was filtered off and from a mixture of methanol and 2.5N hydrochloric acid and subsequently from a mixture of methanol and acetonitrile recrystallized. 3.20 g of 1 - (p-Hydroxyphenyl) -2-phenyl-6- (2-diethylaminoethoxy) -3,4- dihydro-naphthalene hydrochloride with a melting point of 232-236 C. Further recrystallization from the same solvent mixture gave an analytical sample with a melting point 232-235.5 ° C.

Anal calcd for C ₂₈ H _{32 ClNO 2} : C 74.73; H 7.17; Cl 7.88; Found: C, 74.21; H 7.35} Cl 7.96.

A suspension of 1 g of the hydrochloride obtained in 50 ml of ether was treated with aqueous sodium bicarbonate solution shaken, the ether layer separated and evaporated to dryness, whereupon the free i- (p-hydroxyphenyl) -2-phenyl-6- (2-diethylaminoethoxy) -3,4-dihydro-naphthalene received.

The 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone used in Examples 1 and 2 was made as follows:

A solution of 45 g of m-methoxy-acetophenone in 75 ml of 95% ethanol became a cooled solution of 16 g

909829/1572

BATH

H93323

Sodium hydroxide is added to 140 ml of water. The ^U emiüch was put out in an ice bath, and 31 "8 g benzaldehyde are added at such a rate that the temperature below 30 0 remained. After the addition, the mixture was stirred in the cold for 30 minutes and then at about 25 ^° C. for 27 hours. The solution obtained was extracted with ether, the extract was washed with saturated sodium chloride solution, then percolated through anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. Wan received 50.9 g 3 ^! -Methoxy-chalcone in the form of an oil; Bp at 4 mm Hg 180-185 ° C.

A solution of 27.8 g of aluminum cyanide in 50 ml of water was added over a period of 10 minutes to a mixture of 50.9 g of 3'-methoxy chalcone, 13.0 g of acetic acid and 100 ml of 95% ethanol. The temperature was kept at 45 ° C. The mixture was then stirred for 6 hours and left to stand in the cold for more than eight hours. The precipitated pesticide was filtered off, washed with ice-cold aqueous ethanol and with water and recrystallized from ethanol. 49.22 g of 2-phenyl 4_ (3'-methoxyphenyl) -4-keto-butyronitrile were obtained in the form of a crystalline solid from Melting point 96-101 C. The IR spectrum of the compound in mineral oil showed maxima at 2200, 1660 and 1580 cm " ¹ .

A suspension of 49.22 g of 2-phenyl-4- (3'-methoxyphenyl) -4-keto-butyronitrile in a mixture of 140 ml of concentrated sulfuric acid and 125 ml of water was heated on the steam bath with vigorous stirring for 4 hours. The ^UE emiych obtained was cooled and diluted with ice water. The deposited solid was filtered off and recrystallized from aqueous ethanol and then from benzene, giving 29.5 g of 2-phenyl-4- (3'-methoxyphenyl) -4-keto-butyric acid in the form of a crystalline solid with a melting point of 140-145 ° C. An analysis sample that is

BATH 909829/1572

was obtained from benzene, melted at 143-145 C

Anal calcd for C ₁₇ H ₁₆ O ₄ : C, 71.82; H 5.67; found: C, 72.10; H 5.74.,

300 g of zinc sponge were washed briefly with 2.5 η hydrochloric acid and then with water, the metal was then covered with a solution of 6.7 g of mercury chloride in 500 ml of water and the mixture was left to stand for 30 minutes with occasional shaking. The liquid phase was decanted off and the amalgamated metal was washed _{well with water.} A mixture of 29.3 g of 2-phenyl-4- (3'-methoxyphenyl) -3-keto-butyric acid and 400 ml of hydrochloric acid was added to the amalgamated zinc, and the mixture was carefully brought to reflux temperature and refluxed for a total of 20 hours heated, further hydrochloric acid was added after 5 and 10 hours. The mixture obtained was cooled, the liquid was then decanted off from the pesticide, the solid residue was washed well with ether and the decanted liquid was extracted with ether. The ether extract and the washing liquid were combined and washed with water and then with saturated sodium chloride solution. Then percolation was carried out with anhydrous magnesium sulfate. The percolate was evaporated to dryness. 25.2 g of 2-phenyl-4- (3'- methoxyphenyl) butyric acid in the form of a viscous oil, which was processed further without further purification. The IR spectrum of the compound (in mineral oil) showed a maximum at 1705 cm "*

26.2 g of 2-i? Henyl-4- (3'-methoxyphenyl) butyric acid were added to 150 ml of liquid hydrogen fluoride with cooling and shaking. The üemisch obtained wurae 3 -age at room temperature allowed to stand ^ he was dissolved in methylene chloride residue and the solution concentrated in excess

909829/1572 bad original

Poured aqueous sodium carbonate solution. The organic layer was separated, washed with water and saturated sodium chloride solution and then the ^x 'Rockne evaporated. The residue was dissolved in 2 liters of hexane hydrocarbons containing 7-5 "% by volume of acetone, and the solution was chromatographed on a column of synthetic magnesium silicate which had been prewashed with the same mixture of solvents. The eluate was evaporated to dryness and the residue (17.0 g) recrystallized twice from cyclohexane, giving 13.38 g of 2-chenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone in the form of a crystalline compound with a melting point of 113 -116 ⁰ C,

Anal, calculated for ^c - | 7 ^H - | b ° 2 ^{! c} ^ ° »92; II 6.39; Found: C, 81.08; H 6.35.

BATH ORIGINAL

909829/1572

Claims (2)

• H93323 PATENT CLAIMS: 1, 1,2-Diphenyl ~ 3> 4-dihydronaphthalenes of the general formula OM in which M is hydrogen or an alkali metal _t R ^ and R _{2 is} a lower alkyl, lower alkenyl, lower alkoxy or lower alkenyloxy radical, the hydroxyl group, fluorine or chlorine, the '^ rifluormethyl-, a lower alkyl mercapto radical or the group -0 -AN ^ _R 3 mean, where A is an alkylene radical with 2-6 carbon atoms, R, and R, individually lower alkyl radicals or together with the nitrogen atom form a 5- to 7-güedrigen saturated heterocyclic radical and χ and y the numbers 0, 1 or 2 represent, as well as pharmacologically suitable acid addition salts and quaternary ammonium derivatives of the compounds in which H is hydrogen and _n / ■ at least one of the radicals R ^ and R ^ the group -0-A-N ^^ means" 2. 1- (p-Hydroxyphenyl) -2-phenyl-6-methoxy-3,4-dihydronaphthalene and its pharmacologically suitable acid addition salts, 3 «Process for the preparation of the compounds according to claim 1, characterized in that one in itself 909829/1572 U93323 known way is a 1,2,3,4-tetrahydro-2-phenyl-1-naphthalenone the general formula in the Rc and Rg a lower alkyl, lower alkenyl, lower alkoxy ^ lower alkenyloxy or the 2-tetrahydropyranyloxy radical, fluorine or chlorine, the Trifluoromethyl radical, a lower alkyl mercapto radical or the group -0-Α-Ν ^^ 3 mean in the presence of a inert organic solvent with a Grignard weight of the general formula III Mg shark converts, in which Hai represents a halogen atom, optionally carbinol formed dehydrated, the resulting compound of the general formula 909829/1572 Η93323 IV hydrolyzed under acidic conditions and, if appropriate, subsequently converting the compounds obtained into alkali metal salts, acid addition salts or quaternary ammonium compounds. Process according to Claim 3, characterized in that the starting materials used are 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone and p- (2-tetrahydropyranyloxy) phenyl magnesium bromide used. For THE TJPJOHN COlCPANY Kalamazoo (Michigan, VStA *) Rechxsanv / old 909829/1572