IL23284A

IL23284A - Derivatives of 1,2-diphenyl-3,4-dihydronaphthalenes

Info

Publication number: IL23284A
Application number: IL23284A
Authority: IL
Original assignee: Upjohn Co
Priority date: 1964-05-01
Filing date: 1965-04-02
Publication date: 1969-01-29
Also published as: DE1493366C3; CH513092A; NL6505537A; NL147123B; JPS4827320B1; GB1107016A; GB1107017A; DE1493366A1; DE1493366B2

Description

C O H E N Z E D E & S P I S B A C H R EG D. PAT E N T ATT OR N E YS 24, LEVONTIN STR., P. O. B. 1169 P A T E N T S & D E S I G N S O R D I N A N C E SPECIFICATION DERIVATIVES OP 1,2 DIPHENYL 3,4 DIHYDRO PHTALENES 0» 3^Π^3 THE UPJOHN COMPANY, a Corporation of the State Delaware, of 301 Henrietta Street, Kalamazoo , Michigan, U.S.A., REBY DECLARE the nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement : This invention relates to novel reduction products of l,2-diphenyl-j5, dihydronaphthalenes and is more particularly concerned with reduction products of 6-alkoxy-l,2 diphen^l- 2, -dihydronaphthalenes, and derivatives thereof, and processes for their preparation, The novel compounds of the invention and processes for their preparation are shown in the following flow sheet* In the above formulae X is selected from the class consisting of hydrogen, hydroxy, halogen and lower-alkyl; R represents lower-allkylj Ri is selected from the class consisting of hydrogen, lower-alkyl and halogen; and s is selected from the class consisting of hydrogen, hydroxy, halogen, lower-alkyl, lower- alkoxy, lo er-alkoxy substituted by a group selected from the class consisting of (a) dihydroxyalkyl from 2 to 5 carbon atoms, inclusive, (b) 2-amino-l-hydroxyethyl, (c) 5-( 2- and FU taken individually represent lower-alkyl and R3 and taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and the radical -O-Cmlkm-Rs wherein CmH2m is an alkylene radical from 1 to 12 carbon atoms, inclusive, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy .

The term "lower-alkyl" means an alkyl radical of from 1 to 8 carbon atoms, Inclusive, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms thereof The term "halogen" means fluorine, chlorine, bromine, and iodine. The term "lower-alkoxy" means alkoxy containing from 1 to 8 carbon atoms, inclusive, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, and isomeric forms thereof. The term "dihydroxyalkyl from 2 to 5 carbon atoms" is inclusive of 1, 2-dihydroxyethyl, 1, 3-dihydroxypropyl, 2,3-dihydroxypropyl, 1, -dihydroxybutyl, 1, 3-dihydroxybutyl, 1,4-dihydroxypentyl, and the like. The term "alkylene radical from 2 to 6 carbon atoms, inclusive" means ethylene, propylene, butylene, pentylene, hexylene, and isomeric forms thereof. The term "heterocyclic radical of from 5 to 7 ring atoms" is inclusive of pyrrolidino, lower-alkjrlpyrrolidi.no such as 2-methylpyrrolidino, .. 2, 2-dimethylpyrrolidino, 3-methylpyrrolidino, and the like, piperazino, lower-alk lpiperazino such as 2-methylpiperazino, -methylpiperazino, 2, -dime hylpiperazino, and the like, piperidino, lower-alkylpiperidino such as 2-methylpiperidlno, 3-methylpiperidino, , -dime hylpiperidino, and the like, morpholino, hexamethylenimino, homoplperazino, and the like. The term "alkylene radical from 1 to 12 carbon atoms, inclusive" means methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, deGylene, undecylene, dodecylene, and isomeric forms thereof. The term "lower-carbalkoxy" means the group -COOAlkyl wherein Alkyl is lower-alkyl as hereinbefore defined.

The term " ovel compounds of the invention" as used throughout the specification embraces the compounds represented by the formulae(D), (III), (TV) and (V) above, including the acid addition salts and quaternary ammonium salts of said compounds wherein the substituent R∑ contains a tertiary amino group, and the alkali metal and alkaline earth metal salts of the compounds of the formulae (£¾, (113), (IV) and(v) wherein the substituent R2 represents hydroxy.

The acid addition salts of the invention comprise the salts of the basic compounds of formulae (l¾, Qui), (pj) and (V) above with pharmacologically acceptable acids such as sulfuric, hydrochloric, nitric, phosphoric, lactic, benzoic, methane-sulfonic, p-toluenesulfonic, salicylic, acetic, propionic., maleic, malic, tartaric, citric, cyclohexanesulfamic, succinic, nicotinic, ascorbic acids, and the like.

The quaternary ammonium salts of the invention are the salts obtained by reacting the tertiary amino compounds of formulae fe¾ ft ) and (v) with quaternating agents, for example, lower-alkyl halides, lo er-alkenyl halidesj di( lower-alkyl) sulfates, aralkyl halides, lower-alkyl arylsulfonates, and the like. The term "lower-alkyl" has, tiie n meaning hereinbefore defined. The term "lower-alkenyl" means ailkejiy from 3 to 8 carbon atoms, inclusive, such as allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, and isomeric forms thereof. The term "aralkyl" means an aralkyl group containing from 7 to 13 carbon atoms, inclusive, such as benzyl, phenethyl, phenylpropyl, benzhydryl and the like. The term "lower-alkyl arylsulfonates" means the esters formed from lower-alkyl alcohols and arylsulfonic acids such as benzenesulfdnic, toluenesulfonic, xylenesulfonic, and like acids. Examples of quaternary salts of the compounds of the invention are the methobromide, methiodide, ethobromide, propyl chloride', butyl bromide, octyl bromide, methyl methosulfate, ethyl ethosulfate, allyl chloride, allyl bromide, benzyl bromide, benzhydryl chloride, methyl toluenesulfonate, ethyl toluenesulfonate, and the like.

The novel compounds of the invention as defined above possess pharmacological activity. Thus, the novel compounds of the invention are active as antifertility, estrogenic, anti-estrogenic, antispermatogenic, fungicidal, hypocholesteremic lipid-mobllizing and antiprogestational agents and have 3, 4, , 6,7, 8-hexahydro-5, 6-diphenyl-2( lk) -naphthalenone, 6-methoxy- 1-(p -2-pyrrolidinoethoxypheny 1 ) -2-phenyl -1, 2, 3, 4-tetrahydronaphthalene, and 6-methoxy-l, 2, -diphenyl-1, 2,3, , 5, 8 -hexahydronaphthalene exhibit oral antifertility activity in rats when tested by the method described by Duncan et al., Proc. Soc. Exp. Biol. Med. 112, 439-442, 1963.

The novel compounds of the invention are valuable for animal pest control, For example, the compounds of the invention are formulated in combination with baits and/or attractants and placed in feeding stations accessible to undesirable rodents and other small animals including Canidae such as coyotes, foxes, wolves, jackals, and wild dogs and birds such as starlings, gulls, redwing blackbirds, pigeons, and the like, thus reducing hazards to aviation by their presence on runways and in the vicinity of airfields, the spread of disease, and destruction to propert in both rural and urban areas.

For purposes of administration to birds and to mammals, including man and animals of economic value such as horses, cattle, sheep, pigs, mice, rats, rabbits, and the like, the novel compounds of the Invention can be combined with solid or liquid pharmaceutical carriers and formulated in the form of tablets, powder packets, capsules, and like solid dosage forms, using starch and like excipients, or dissolved or suspended in suitable solvents or vehicles, for oral or parenteral administration.

In addition to their pharmacological activity, the compounds of the invention are also useful as intermediates, For example, the basic compounds having the formulae frl), (H& (IV) and((V) can be reacted with fluosilicic acid to form the fluosilicate salts which in dilute aqueous solution are effective mothproofing agents as more fully disclosed in U. S. Patents 2, 075, 559 and 1, 91 , 33^ .

The novel compounds of the invention are prepared in accordance with the reactions shown in the flowsheet above.

The l, 2-diphenyl-6-alkoxy-3, -dihydronaphthalenes (I) employed starting materials are subjected to reduction by methods well known in the art for the saturation of ethenoid bonds to give the corresponding 1,2,3, -tetrahydronaphthalenes (II) . The reduction can be effected using reducing agents such as sodium the presence of an alkanol, for example, methanol, ethanol, propanol, isobutyl alcohol, and the like, and lithium and like alkali metals in the presence of liquid ammonia. The use lithium and liquid ammonia is the preferred method of effecting the reduction of (I) to (II).

Using the latter reducing agent the reduction can be carried out by adding an approximately stoichiometric amount of lithium, advantageously in the form of lithium wire, to a solution of the dihydronaphthalene (I) in a mixture of liquid ammonia and an inert organic solvent such as tetrahydrofuran, benzene, toluene, ethanol, methanol, isobutylaalcohol, tertiary butyl alcohol, and the like, or a mixture of such solvents.

The reduction occurs rapidly and is usually substantially complete in a period of from about 15 minutes to about 1 hourj though longer reaction periods may be necessary with certain compounds. The desired product (II; R2=X) is isolated from the reaction mixture by conventional procedures ; for example, by evaporation of the solvent after addition of ammonium chloride, followed by solvent extraction of the residue, evaporation of solvent from the extract, and purification of the resulting product by recrystallization, chromatography, or like conventiona procedures.

The thus-obtained compounds of formula (II) wherein R2 is hydroxy can then be converted to other compounds of the invention having the formula (II) wherein R2 is etherifled- hydroxy by conventional procedures. For example, the compounds (13) (R2e0H) can be alkylated by methods well known in the art for the etherification of phenols. Illustratively, the compounds of lower-alkoxy or tertiaryaminoalkoxy ¾, R4 and ΟηΗδη are as hereinbefore by treating the corresponding compounds of formula (il) wherein R2 is hydroxy with the approhalide or tertiaryaminoalkyl halide herein ¾, R4 and CnH2n are as hereinbefore halogen^ preferably bromine or iodine) in the presence of a base such as sodium hydroxide, sodium methoxide, and the like. The etherification is conducted advantageously in the presence of an inert organic solvent such as tetrahydrofuran, dioxane, a lower-alkanol, for example, methanol, ethanol, isopropyl alcohol, and the like.

The carboxyalkyl and carbalkoxyalkyl ether compounds of formula (II) wherein Rz is -0-CmH2m-R5 (wherein R5 and CmH2m are as hereinbefore defined) can be prepared by reaction of the appropriate halo ester, HHal-CmHsm-Rs wherein Hal represents halogen, preferably chlorine or bromine, and R5 is carbalkoxy, with an alkali metal salt, preferably sodium or potassium salt, of the corresponding phenol (II; R2=0H) . The reaction is carried out in the presence of an inert organic solvent such as tetrahydrofuran, dimethylformamide, benzene, toluene, xylene, and the like, using conditions conventional in the art for such alkylations. The carbalkoxyalkyl ether (II) so obtained can be hydrolyzed to the corresponding free acid using conditions known in the art for hydrolysis of carboxylic acid esters, for example, by treatment with aqueous or alcoholic alkali metal hydroxides.

Similarly the compounds of formula (II) wherein R2 is a lower-alkoxy group substituted by dlhydroxyalkyl as hereinbefore defined, or by epoxyethyl, can be prepared by alkylating the corresponding compounds of formula (II) wherein R2 is hydroxy with the appropriate dihydroxyalkyl halide or eppxyalkyl halide in the presence of a base such as sodium hydroxide, sodium methoxide, and the like. The alkylation is conducted advantageously in the presence of an inert organic solvent such as tetrahydrofuran, dioxane, a lower-alkanol, for example, methanol, ethanol, isopropyl alcohol, and the like.

The compounds so obtained wherein R2 represents lower-alkox substituted by epoxyethyl can be reacted with succinimide in the presence of a base such as pyridine, piperidine, N-methyl-piperidlne, and the like, whereby the epoxy ring is opened and the corresponding 2-succinimido-l-hydroxyethyl-substituted lower-alkoxy compound is obtained. The latter compound is subjected to alkaline hydrolysis, for example, using aqueous1 or alcoholic sodium or potassium hydroxide, to yield the corresponding compound of formula (II) wherein R2 is lower-alkoxy substituted by 2-amino-l-hydroxyethyl.

The latter compound is converted to the corresponding oompound of formula (.II) wherein R2 is lower-alkoxy substituted n by 5-(2-thio¾i!o0xazolidinyl) - by reaction with carbon disulfide in the presence of a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, and the like. The procedures employed can be those described in the art; see, for example, Bruson et al., J. Amer. Chem. Soc. 59, 2011, 1937· The reactio is preferably conducted in the presence of an inert organic solvent such as tetrahydrofuran, dioxane, ethanol, isopropyl alcohol, and the like. Elevated temperatures, e.g., the reflux temperature of the reaction mixture, are advantageously employed in the condensation.

Similarly, the compounds of formula (II) wherein R2 represents lower-alkoxy substituted by 5-( 2-oxo0xazolidinyl) -are prepared from the corresponding compounds wherein R2 represents lower-alkoxy substituted by 2-amino-l-hydroxyeth l b reacting the latter compounds with ethyl chloroformate, phosgene, or a dialkyl carbonate in the presence of a base using procedures known in the art; see, for example, :, .

U. S.- Patent..2, 399, 188.

The compounds of the invention having the formula (III): Wherein Ra is hydrogen, hydroxy, loWer-alkyl or halogen obtained by subjecting the corresponding compounds having the formula (II) to a Birch reduction. The latter reductive procedure, named after A. J. Birch who was responsible for its discovery, involves -the use of lithium in liquid ammonia as the reducing agent. The procedure under which this reaction is carried out, which procedure is employed in the context of the present invention, has been extensively reviewed in the literature; see, for example, Quarterly Reviews.4, 69, 1950; ibid., 12, 17 , 1958. Generally speaking, the Birch reduction is carried out in the context of the present invention by adding metallic lithium, preferably in the form of a wire, portionwise to a solution of the compound (II) in a mixture of liquid ammonia and a combination of inert organic solvents one of which is an ether such as tetrahydrofuran, diethyl ether and dioxane, and the other is an alkanol such as ethanol, isopropyl alcohol, butanol, t-butyl alcohol, and the like. The lithium is preferably employed in excess of the stoichiometric proportio advantageously in an excess of the order of about 10 gram-atoms of lithium per mole of compound (II). When the reduction is substantially complete, as determined by analytical techniques r d e 1992 mixture is treated with ammonium chloride and the solvents are removed by evaporation. The desired compound (III) is Isolated from the residue by conventional techniques, for example, treatment with water followed by isolation of the insoluble material by filtration and purification by recrystallization, chromatography, and like techniques.

The compounds (III) wherein Ra represents etherifled hydroxy are readily prepared by etherification of the appropriately substituted compound (III) wherein Ra represents hydroxy. The etherification to produce the various ethers is carried out using the procedures described above for preparation of the corresponding ethers of formula (II) .

The compounds of the invention having the formula (IV) are obtained conveniently by acid hydrolysis of the corresponding compounds of formula (ill) . The hydrolysis can be carried out in aqueous or aqueous alcoholic solutions using dilute mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, and the like, or preferably using organic acids such as oxalic acid, acetic acid, propionic acid, . arid\;the like. The hydrolysis is carried out advantageously at or below room temperature o (approximately 20 to 25 C). The hydrolysis of the enol ether group at position 6 and rearrangement with formation of the resulting 6-keto compound (IV) can be followed by analytical techniques such as infrared spectral analysis. When the reaction is substantially completed, as shown by said analytical techniques, the desired compound (IV) is isolated from the reaction mixture by conventional techniques, for example, by neutralization followed by evaporation of the solvent. The residue is subjected to solvent extraction or like techniques to isolate the compound (IV), which latter is purified by convention · The compounds (IV) wherein R≥ represents etherified hydroxy can be prepared by direct hydrolysis of the corresponding compounds of formula (III) or can be prepared by etherification of the corresponding compounds (IV) wherein R2 is hydroxy, using the procedures described above for the preparation of the corresponding ethers of formula (II).

The compounds of the invention having the formula (V) are obtained by rearrangement of the corresponding compounds of formula (IV). Said rearrangement is carried out by treating the compound (IV) with strong mineral acid such as concentrated hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or the like, or by treatment with strong base such as sodium hydroxide, potassium hydroxide, potassium ethoxide, sodium methoxide, and the like. The reaction is advantageously carried out in concentrated aqueous or alcoholic solution at approximately the boiling point of the reaction mixture. When the rearrangement is substantially complete, as determined by infrared or like analytical techniques, the desired compound (V) is isolated from the reaction mixture by conventional techniques such as by neutralization followed by evaporation to dryness and purification of the residue by conventional techniques such as solvent extraction, countercurrent distribution, chromatography, recrystallization, and the like, or any combination of these techniques.

The compounds of formula (V) wherein R2 represents etherified hydroxy can be prepared by etherification of the corresponding compounds (V) wherein R2 is hydroxy or by direct rearrangement of the corresponding etherified compounds (IV) . The etherification of the hydroxy group is carried out using the etherification procedures described above for the re arat on of the corres ondin ethers of formula I .

The acid addition salts of the compounds of the invention, i,e., the acid addition salts of those compounds of formulae (E¾, (ΠΪ3), (XV) and (5j which are basic, can be prepared by methods well known in the art. For example, the acid addition salts of the basic compounds of the invention can be prepared by reacting said basic compounds with a pharmacologically acceptable acid, as hereinbefore exemplified, in the presence of an inert solvent such as methanol, ethanol, diethyl ether, ethyl acetate, and the like.

The quaternary ammonium salts of the invention, i.e., the quaternary ammonium salts of the tertiary amino compounds[ of formulae M and (v) can be prepared by reacting the tertiary amino compound with a quaternating agent, for example, an alkyl halide such as methyl iodide, ethyl chloride,!.:,; isopropyl bromide, and the like, an alkenyl halide such as allyl chloride, allyl bromide, and the like, a dialkyl sulfate such as dimethyl sulfate, diethyl sulfate, and the like, an aralkyl halide such as benzyl bromide, benzhydryl chloride, phenethyl bromide, and the like, or an alkyl arylsulfonate auch as methyl p-toluenesulfonate, and the like. Preferably the reactio is effected by heating the reactants together in the presence of an inert solvent such as acetonitrile, acetone, methanol, ethanol, and the like. Generally speaking, the desired quaternary salt separates from solution upon cooling the reaction mixture and can be isolated by filtration. Purifi-cation of the quaternary salt can be effected by conventional methods, for example, by recrystallization.

The anion of the quaternary ammonium salt obtained as described above can be exchanged for any other desired anion, e.g., the anions of the various acids enumerated previously, by conventional procedures. For example, any of the quaternary ammonium salts of the invention can be converted to the corresponding quaternary ammonium hydroxide, illustratively by treatment with silver oxide, and the hydroxide so obtained is reacted with the appropriate acid to obtain the desired quaternary ammonium salt .

The metal salts of the invention, namely the alkali metal and alkaline earth metal salts of the compounds of the formulae (EH), (H¾i and 0 wherein R2 represents free hydroxy, can be prepared by conventional procedures, for example, by neutralizing the appropriate phenol with an appropriate alkali metal hydroxide, or carbonate, or an alkaline ''·'-earth metal hydroxide, in aqueous or aqueous alcoholic solution followed by evaporation to dryness of the resulting solution.

The compounds having the formula (I) which are employed as starting materials in the process of the invention can be prepared according to the following reaction scheme: (I) In the above formulae R and ¾. have the significance hereinbefore defined.

In the above reaction sequence, the appropriately- substituted acetophenone is condensed with the appropriately substituted benzaldehyde (VTl) to produce the corresponding chalcone (VIIl) under conditions conventionally employed in the preparation of chalcones, for example, by condensation of (VI) and (VTjJin the presence of a base such as sodium hydroxide, potassiu hydroxide, and the like, in an inert solvent such as a mixture of water and a lower alkanol, for example, methanol, ethanol and the like . The reaction is generally conducted at or below room o temperature ( approximately 20 to 25 C . ) with external cooling as required . The chalcone (VIIl) is Isolated from the reaction mixture and purified by conventional procedures, for example, by solvent extraction followed by distillation, in the case of a liquid product, or re crystallization in the case of a solid product .

The chalcone (VIII) so obtained is then converted to the corresponding nitrile (IX) by reaction with hydrogen cyanide, for example, by treatment with an alkali metal cyanide such as potassium cyanide, sodium cyanide, and the like, in the presence of acetic acid and an inert solvent such as aqueous me thanol, aqueous ethanol, and the like, using the procedure described by Newman, J. Am. Chem. Soc . 60, 29 γ, 1938 for the conversion of benzalacetophenone ( chalcone) to a-phenyl^-benzoylproploiiitrile . The desired nitrile (IX) generally separates from the reaction mixture as a solid and can be isolated by filtrati on and purifie by recrystallization .

The nitrile (ix) so obtained is hydrolyzed to the correspondi keto acid (x) by conventional procedures for the hydrolysis of nitriles, for example, by heating under:. -reflux in the presence of aqueous mineral acid such as sulfuric acid until hydrolysis is substantially complete . The desired acid (X) generally separat from the reaction mixture as a solid and is isolated by filtration and purified by recrystallization or by other conventional procedures, for example, by conversio to an alkali metal salt followed by acidification of the latter to regenerate the free acid.

The keto acid (X) so obtained is then subjected to reduction to form the corresponding acid (X]). The reduction can be effected using any of, the methods customarily employed for the conversion of a keto group to a methylene group. A particularly suitable reducing agent is amalgamated zinc; for. example, treatment of the keto acid (X) ith amalgamated zinc in the presence of a mineral acid affords the desired acid^(X]) in excellent yield. The acid (X¾ can be isolated from the reaction mixture by conventional procedures, for example, by decantation of the liquid reaction mixture, followed by solvent extraction of the decanted liquid and evaporation of the solvent. Generally speaking, the acid(X¾ so obtained is sufficiently pure to be used in the next step of the synthesis without further treatment.

If desired, however, the acid so obtained can be purified by conventional procedures, for example, by distillation in the case of a liquid or recrystallization in the case of a solid, or by conversion to an alkali metal salt followed by acidification of the latter to yield the free acid.

In the next stage of the synthesis the acid(X¾ is cyclized to the required a-tetralone (XI3) in the presence of a Lewis acid using the general procedure described by Fieser and Hershberg, J. Am. Chem. Soc. 61, 1272, 19,59 » The term "Lewis acid" is well known in the art and is defined succinctly by Fieser and Fieser, "Organic Chemistry", Third Edition, page 138 (Reinhpld, 1956) . Examples of such compounds are hydrogen fluoride, boron trifluoride, arsenic trifluorlde, phosphorus pentafluoride, titanium tetrafluoride, concentrated, sulfuric acid, polyphosphoric acid, and the like. The preferred Lewis acid for use in the above process is hydrogen fluoride.

A particularly convenient method of cyclizing the acid(XI) according to the above procedure comprises adding the acid (JCt) to liquid hydrogen fluoride with stirring and then allowing o the hydrogen fluoride to evaporate at about 20 to 30 C. The desired α-tetralone (XII) is then isolated from the residue by conventional methods, for example, by dissolving the residue in a suitable solvent such as diethyl ether, washing the solution 0 so obtained with an aqueous solution of a base such as sodium carbonate, sodium hydroxide, and the like, and then evaporating the washed solution to dryness. The a-tetralone (Xl¾ so obtained can be purified, if desired, by conventional procedures, for example, by recrystallization.

Alternatively, the acid fXE) can by cyclized to the α-tetralone (XII) by conversion of the acid(xi) to the corresponding acid chloride and treatment of the latter with aluminum chloride or stannic chloride according to the procedure described by Fieser et al,, J. Am. Ghem. Soc. 60, 170, 1938. o The α-tetralone (XII) is condensed with the appropriate Grignard reagent ""^""^-MgHal wherein X is .as hereinbefore defined with the exception noted below, and Hal represents halogen, preferably bromine or iodine,, to give the corresponding compound (I). The reaction is carried out under conditions ^ normally employed in conducting Grignard reactions. Thus, the reaction is carried out under anhydrous conditions, advantageously in the presence of an inert solvent such as dibutyl ether, , diisopropyl ether, tetrahydrofuran, and the like. The preferred solvent is tetrahydrofuran. The reaction can be carried out at o Q temperatures within the range of about 0 C. to about the boiling point of the sol-vent employed, and preferably is carried out o o within the range of about 15 to about 30 C.

The desired product (I) can be Isolated from the reaction mixture by conventional procedures^ For example, the reaction mixture from the above-described Grlgnard reaction is decomposed by the addition of water, ammonium chloride, and the like, followed by separation of the organic layer and removal of the solvent therefrom. The residue is purified, if desired, by conventional procedures, for example, by chromatography, recrystallization, and the like.

In preparing the compounds (I) wherein X represents hydroxy from the corresponding a-tetralone (XII) it is necessary to employ a Grlgnard reagent in which the group X represents a protected hydroxy group from which the free hydroxy can be regenerated subsequently, A convenient manner in which this preparation can be effected is to employ a Grlgnard reagent formed from the tetrahydropyranyl ether of the appropriate halophenol. The reaction of such a Grlgnard reagent with the a-tetralone (XII) gives rise to the desired compound (I) wherein the hydroxy group is still protected aa the tetrahydropyranyl ether. The ether grouping is readily removed by mineral acid hydrolysis and where the working up procedure from the Grlgnard reaction employs the use of mineral acid, said ether is often removed during the working up withou the need to introduce a separate hydrolysis step.

The Grignard reagents employed in the conversion of the a-tetralones (XII) to the compounds (I) are prepared by reaction of magnesium in an anhydrous inert organic solvent such as dibutyl ether, diisopropyl ether, tetrahydrofuran, and the like, with the appropriately substituted halobenzene, using procedures The acetophenones (VI) which are employed as starting materials in thet:.above-described synthesis of the a-tetralones (XII) can be prepared from the corresponding nuclear-substituted tenzoic acids by conversion of the latter to the acid chlorides followed by reaction of the latter with dimethyl cadmium according to the procedure described in Chemical Reviews 40, , 19 7. Many of the acetophenones (!¾!) are known in the literature .

The benzaldehydes (3CII) which are employed as starting materials in the above-described synthesis of the a-tetralones (XII) can be obtained by reduction of the corresponding substituted benzoyl chlorides using lithium tri-t-butoxyaluminum hydride using the procedure described by Brown et al., J. Am.

Chem. Soc. 80, 5577, 1958 . Many of the benzaldehydes of the formula (VII) are known in the literature.

An alternative method for the preparation of the a-tetralones of formula (XII) is that described by Newman, J. Am. Chem. Soc. 6¾- 2295, .19 0.. The method comprises reacting the appropriately substituted benzyl cyanide with the appropriately substituted phenethyl bromide Rx and R having the significance hereinbefore defined, in the presence of sodamide and hydrolyzing the resulting nitrile to give the corresponding acid (XI) which is then cyclized as hereinbefore described to the a-tetralone (XII) .

The following preparations and examples illustrate the best d e e e Preparation 1 3 ' -raethoxychalcone A solution of 5 g. ;of m-methoxyacetophenone in 75 ml. of 9 $ ethanol was added to a cooled solution of 16 g. of sodium hydroxide in l40 ml, of water. The mixture was then placed in an ice bath and 31.8 g. of benzaldehyde was added at such a o rate as to keep the temperature below 20 C. The mixture was stirred for an additional 30 minutes in the cold and was then o stirred for 27 hours at about 25 C. The resulting solution was extracted with ether and the extract was waslied with saturated sodium chloride solution before being percolated through anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. There was thus obtained 50.9 g. of 3' -methoxychalcone o in the form of an oil having a boiling point of 180 to 185 C. at a pressure of mm. of mercury.

Using the above procedure, but replacing m-methoxyacetopheno by the following compounds: m-ethoxy-, m-pentyloxy- (prepared by etherification of m-hydroxyacetophenone with pentyl bromide), m-hexyloxy- (prepared from m-hydroxyacetophenone by etherificatio t with hexyl bromide), and m-isooctyloxyacetophenone (prepared from m-hydroxyacetophenone by etherification with isooctyl bromide), there are obtained 3'-ethoxy-, 3 » -pentyloxy-, 3' -hexyloxy-, arid 3' -isooctyloxychalcone, respectively.

Similarly, using the procedure described in Preparation 1, but replacing benzaldehyde by the following known compounds: 2-bromobenzaldehyde, 3-chlorobenzaldehyde, 2-chloro-6-fluorobenzaldehyde, 2, 3-dichlorobenzaldehyde, p-tolualdehyde, . and 2, 6-dimethylbenzaldehyde, there are obtained 2-bromo-3 ' -methoxychalcone, 3-chloro-3 ' -methoxychalcone, 2-chloro-6-fluoro- 3 ' -methoxychalcone, 2, 3-dichloro-3 ! -methoxychalcone, 4-methyl-3' -methoxychalcone and 2, 6-dimethyl -3 ' -methoxychalcone, res ectivel .

Preparation 2 2-phenyl-4-(3-methoxyphenyl) - -ketobutyronitrlle A solution of 27.8 g. of potassium cyanide in 50 ml. of water was added to admixture of 50.9 g. of 3 ' -methoxychalcone, 15,0 g. of acetic acid, and 100 ml. of 95# ethanol over a o period of 10 minutes. The temperature was maintained at 5 C.

The turbid mixture was then stirred for 6 hours and allowed to stand overnight in the cold. The crystalline solid which had separated was isolated by filtration, washed with ice-cold aqueous ethanol and with water, and recrystallized from ethanol. There was thus obtained 49.22 g. of 2-phenyl-4-( 3-methoxyphenyl) - 4-ketobutyronitrlle in the form of a crystalline solid having o a melting point of 96 to 101 C. The infrared spectrum of the compound (mineral oil mull) exhibited maxima at 2200, ΐ6βθ, and I58O reciprocal centimeters.

Using the above procedure, but replacing 31 -methoxychalcone by 3 ' -ethoxy-, 31 -pentyloxy-, 3 ' -hexyloxy-, 3* -isooctyloxy-, 2-bromo-3 ' -methoxy-, 3-chloro-3 ' -methoxy-, 2-chloro-6-fluoro-3 ' -methoxy-, 2,3-dichloro-3 ' -methoxy-, 4-methy1-3 ' -methoxy-, and 2, 6-dimeth 1-3 * -methoxychalcone, there are obtained 2-phenyl-4-( 3-ethoxyphenyl) -4-ketobutyronitrlle, 2-phe yl -4 -( 3-pentyloxyphenyl) -4-ketobutyronitrile, 2-phenyl-4-( 3-hexyloxypheny -ketobutyronitrlle, 2-phenyl -4-( 3-lsoo*ctyloxyphenyl) -4-ketobutyronitrlle, 2-(2-bromophenyl) -4-(3-methoxyphenyl) -4-ketobutyronitrile, 2-(3-chlorophenyl) -4-( 3-methoxyphenyl) -4-' ketobutyronitrlle, 2-(2-chloro-6-fluorophenyl) -4-( 3-methoxyphenyl 4-ketobutyronitrile, 2-(2, 3-dichlorophenyl) -4-( 3-methoxyphenyl) -4-ketobutyronitrile, 2-p-tolyl-4-( 3-methoxyphenyl) -4-ketobutyronitrile, and 2-(2, 6-dimeth lphenyl) -4-( 3-methoxyphenyl) 4-ketobutyronitrile, respectively.

Preparation 3 2-phenyl-4-( 3-methoxyphenyl) -4-ketobutyric acid A suspension of 49.22 g. of 2-phenyl-4-(3-methoxyphenyl) - sulfuric acid and 125 ml. of water was heated on a steam "bath with vigorous stirring for 4 hours. The resulting mixture was cooled and diluted with ice water. The solid which separated was isolated by filtration and recrystallized from aqueous ethanol and then from benzene. There was thus obtained 29.5 g. of 2-phenyl-4-(3-methoxyphenyl) -4-ketobutyric acid in the form o of a crystalline solid having a melting point of 140 to 145 C. - o Am analytical sample having a melting point of 145 to 145 C. was obtained by recrystallization from benzene.

Anal. Calcd. for Ci7Hx e04 : C, 71.82; H, 5.67.

Found: C, 72.10; H, 5.7^ · Using the above procedure, but replacing 2-phenyl-4-(3-methoxyphenyl) -4-ketobutyronltrile by the appropriately substituted 2, 4-diphenyl-4-ketobutyronitrile (prepared as described in Preparation 2) , there are obtained 2-phenyl - -(3-ethoxyphenyl) -4-ketobuJ;yric: .acid, 2-phenyl-4-(3-pentyloxyphenyl) -4-ketobutyric acid, 2-phenyl -4-( 5-hexyloxyphenyl) -4-ketobutyric acid, 2-phenyl-4-(3-iso¾ctyloxyphenyl) -4-ketobutyric acid, 2-( 2-bromophenyl) -4-(3-methoxyphenyl) -4-ketobutyric acid, 2-(3-chlorophenyl) -4-( 3-methoxyphenyl) -4-ketob ,tryic acid, 2-( 2-chloro-6-fluorophenyl) -4-( j5-methoxyphenyl) -4-ketobutyric acid, 2-( 2, 3-dichlorophenyl) -4-(3-methoxyphenyl) -4-ketobutyric acid, 2-p-tolyl-4-(5-methoxyphenyl) -4-ketobutyric acid and 2 -( 2, 6-dimethylphenyl) -4-( 3-methoxyphenyl) -4-ketobutyric acid, respectively.

Preparation 4 2-phenyl-4-(5-methoxyphenyl)butyric acid A total of 300 g.. of mossy zinc was washed briefly with 2.5 N hydrochloric acid and then with water. The metal was covered with a solution of 6.7 g. of mercuric chloride in 500 ml. of water, and this mixture was allowed to stand for minutes with occasional shaking. The liquid phase was decanted and the amalgamated metal was washed well with water.

To the amalgamated zinc so produced was added a mixture of 9.-5 g. of 2-phenyl-4-(3-methoxyphenyl) -4-ketobutyrlc acid and 00 ml. of hydrochloric acid. The mixture was heated cautiously to reflux temperature and then heated under reflux for a total of 20 hours, additional portions of hydrochloric acid being added after 5 hours and 10 hours of heating. The resulting mixture was cooled and the liquid was decanted from the solid.

The solid residue was washed well with ether and the decanted liquid was extracted with ether. The ether extract and washings were combined and washed with water and then with saturated sodium chloride solution before being percolated through anhydrous magnesium sulfate. The percolate was evaporated to dryness. There was thus obtained 26.2 g. of 2-phenyl-4-(3-methoxyphenyl) utyric acid in the form of a viscous oil which was employed without further purification in the process of Preparation 5· The infrared spectrum of the compound (mineral oil mull) exhibited a maximum at 1705 reciprocal centimeters.

Using the above procedure, but replacing the 2-phenyl-4- (3-methoxyphenyl) -4-ketobutyric acid by the appropriately substituted 2, -diphenyl-4-ketobutyrlc acid (prepared as described in Preparation )» there are obtained 2-phenyl-4-(3-ethoxyphenyl) -, 2-phenyl-4-(3-pentyloxyphenyl) -, 2-phenyl-4-(3-hexyloxyphenyl) -, 2-phenyl-4-(3-iso5ctyloxyphenyl) 2-(2-bromophenyl) -4-(3-methoxyphenyl) 2-(3-chloit?ophenyl) -4-(3-methDxyphenyl) -, 2-(2-chloro-6-fluorophenyl)-4-(3-methoxyphenyl)-, 2-(2,3-dichlorophenyl) -4-(3-me hoxyphenyl) 2-p-tolyl-4-(3-methoxyphenyl}-, and 2-(2,6-dimethylphenyl) -4-( -methoxyphenyl) -butyric acids, respectively.

Preparation 5 2-phenyl -6-methoxy-l, 2, 5,4- tet ahydro -1^naphthalenone A total of 150 ml. of liquid hydrogen fluoride was added to 26 .2 g. of 2-phenyl-4-(5-methoxyphenyl)butyric acid with cooling and swirling. The iireaulting mixture was allowed to stand at room temperature for 3 days. The residue was dissolved in methylene chloride and the solution was poured into excess concentrated aqueous potassium carbonate solution. The organic layer was separated, washed with water and saturated sodium chloride solution, and then evaporated to dryness. The residue was dissolved in 2 1. of mixed hexanes (Skellysolve B) containing 7 · 5# by volume of acetone and the solution was passed through a column of magnesium silicate (Florisil) prewashed with the same solvent mixture. The eluate was evaporated to dryness and the residue ( 17 .0 g.) was recrystallized twice from cyclohexane. There was thus obtained I5 .58 g. of 2-phenyl -6-methoxy-l, 2, 5,4-tetrahydro-l-naphthalenone in the form of a o crystalline solid having a melting point of 115 to 116 C.

Anal. Calcd. for Ci7Hie02 : C, 80.92 ; H, 6.59 - Found: C, 81.08 ; H, 6 .55 - Using the above procedure, but replacing 2-phenyl-4 -( 5 -methoxyphenyl)butyric acid by the appropriately substituted 2, 4-diphenylbutyric acid (prepared as described in Preparation 4) , there are obtained 2-phenyl-6-ethoxy-, 2-phenyl-6-pentyloxy-2-phenyl -6-hexyloxy-, 2-phenyl -6-lsooctyloxy-, 2 -( 2-brompphenyl) β-methoxy-, 2 -( 5-chlorophenyl) -6-methoxy-, 2-( 2-chloro-6-fluorophenyl) -6-methoxy^, 2-( 2, 5-dichlorophenyl) -6-methoxy-, 2-p-tolyl -6-methoxy-, and 2- ( 2, 6-dimethylphenyl) -6-methoxy-1, 2, 5,4-tetrahydro-l-naphthalenones, respectively.

Preparation 6 1, 2-diphenyl -6-methoxy -5, -dihydronaphthalene A solution of 5.04 g. .02 mole of 2- hen l-6-me hox - was added to an ice-cooled solution of the Grignard reagent prepared from 31 .4 g« ( 21 ml.) of bromobenzane and 4 .90 g. of magnesium in 200 ml. of ether. The resulting mixture was o allowed to stand at room temperature (approximately 20 G.) for 16 hours before being decomposed by the careful addition of water. The mixture so obtained was filtered and the organic filtrate was washed with water and with saturated sodium chloride solution before being dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was evaporated to dryness. The residual gum was dissolved in methylene chloride and chromatographed twice over magnesium silicate (Florisll), The columns were eluted with petroleum ether containing increasing proportions of acetone and those fractions which, on the basis of paper chromatographic analysis, were found to contain the desired product were combined and evaporated to dryness. The fractions so obtained from the second chromatography were recrystallized from aqueous methanol. There was thus obtained 2 .5 g. of l, 2-diphenyl-6-methoxy-l, 2, 3, 4-tetrahydro-l-naphthol in the form of a crystalline-solid having a melting point of 112 to o 116 C. An analytical sample having a melting point of 113 to o 116 C. was obtained by further recrystallization from petroleum ether.

Anal. Calcd. for C23H22O2: C, 82.98 ; H, 6 .96 .

Pound: C, 8? .6θ; H, 6 .93 .

A solution of 1 g. of l, 2-diphenyl-6-methoxy-l, 2, 3, 4-tetrahydro-l-naphthol (prepared as described above) and 0. 1 g. of p-toluenesulfonic acid in 100 ml. of toluene was heated for 5 hours at reflux under a Dean-Starke water trap. The solvent was then distilled from the reaction mixture and the residue was dissolved in ether. The ethereal solution was washed with saturated aqueous sodium bicarbonate solution, then with water, and finally with saturated sodium chloride solution.

The washed ether solution was evaporated to dryness and the residue was recrystallized twice from Skellysolve B. There was thus obtained 0.52 g. of l, 2-dlphenyl-6-methoxy-;5i -dihydronaphthalene in the form of a crystalline solid having o a melting point of 90 to 92 C.

Anal. Calcd. for C23HaoO: C, 88 Λ2; H, 6.^5 Found: C, 87 -99 ; H, 6.78.

Using the above procedure but replacing 2-phenyl -6-methoxy-1, 2, 2, -tetrahydro-lHiaphthalenone by 2 -phenyl -6-ethoxy-, 2-phenyl -6-pentyloxy-, 2 -phenyl -6-hexyloxy-, 2-phenyl -6-isooctyloxy-, 2 -( 2-bromophenyl).-6-methoxy-, 2 -( 5-chlorophenyl) -6-methoxy-, 2 -( 2-chloro-6-fluorophenyl) -6-methoxy-, 2-( 2,3-dichlorophenyl) -6-methoxy-, 2 -{p-tolyl) -6-methoxy-, and 2 - ( 2 , 6-dimethylphenyl) -6-methoxy-1, 2, 5, 4- tetrahydro-l-naphthalenone, there are obtained 1, 2-diphenyl -6-ethoxy-, 1, 2 -diphenyl -6-pentyloxy-, 1, 2 -diphenyl -6-hexyloxy-, 1, 2 -diphenyl -6-isottctylpxy-, 1-phenyl -2 -( 2-bromophenyl) -6-methoxy-, l-phenyl-2-( 3-chlorophenyl) -6-methoxy-, 1-phen l-2-( 2-chloro-6-fluorophenyl) -6-methoxy-, 1-phenyl-2-(2, 3-dichloropheny1) -6-methoxy-, l-phenyl-2-(p-tolyl) -6-methoxy-, and 1-phenyl-2-(2, 6-dlme hylphenyl) -6-methoxy- 3, 4-dihydronaphthalene, respectively.

Preparation 7 l-(p-hydroxyphenyl) -2-phenyl- 6½iethoxy-3*4-dihydronaphthalene A solution of 5·83 g. of 2-phenyl-6-methoxy-l,2,3,4-tetrahydro-l-naphthalenone in 75 ml. of tetrahydrofuran was added to a tetrahydrofuran solution containing 0.0247 mole of the Grignard reagent prepared from p-bromophenyl tetrahydropyrany ether (Parham et al., J. Am. Chem. Soc. 70, 4187, 1948) . The resulting mixture was heated under reflux for 16 hours. At the end of this time the mixture was cooled and 10 ml. of water was added. The resulting mixture was filtered and the filtrate was diluted with ether. The organic layer was separated, washed well with water, and dried over anhydrous sodium sulfate. 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 again treated with the Grignard reagent as described above. The reaction mixture from the second Giignard reaction was worked up exactly as described for the first reaction mixture. The gum so obtained was dissolved in 200 ml. of benzene containing 200 mg. of p-toluenesulfonic acid and the mixture was heated under reflux under a Dean-Starke water trap until no further water was collected in the trap.

The solvent was removed from the solution by distillation under reduced pressure and the residue was dissolved in a mixture of 200 ml. of acetone and 70 ml. of 0.5 N hydrochloric acid. The solution so obtained was allowed to stand for 2 hours at room temperature (about 25 C,) and then extracted with ether. The organic iayer was separated and extracted with 5# aqueous potassium hydroxide solution. The aqueous alkaline extract was acidified by the addition of hydrochloric acid and the solid which separated was isolated by filtration.and dried. The material 90 obtained was dissolved in methylene chloride and chromatographed on a column of Plorisil (magnesium silicate) . The column was eluted with Skellysolve B oontaining increasing proportions of acetone and those fractions which, on the basis of infrared and papergram analysis, were found to contain the desired compound were combined and evaporated to dryness. The residue was recrystallized twice from cyclohexane.

There was thus obtained 0.71 g. of l-(p-hydroxyphenyl) -2-pheny - 6-methoxy-3y4-dihydronaphthalene in the form of a crystalline : o solid having a melting point of 130 to 131.5 C.

Anal. Calcd. for C2aH2o02: C, 84.12; H, 6.14.

Found: C, 83.64; H, 5.96.

Using the procedure described above but replacing 2-phenyl-6-methoxy-l, 2, 3, -tetrahydro-l-naphthalenone by 2-phenyl-6-ethoxy-, 2-phenyl-6-pentyloxy-, 2-phenyl-6-hexyloxy-, 2-phenyl-6-iso8ctyloxy-, 2 - ( 2-bromophenyl) -6-methoxy-, 2-( 3-chlorophenyl) -6-methoxy-, 2 -( 2-chloro-6-fluorophenyl) -6-methoxy-, 2 - ( 2 , 3-dichloropheny 1) -6-methoxy-, 2-(p-tolyl) -6-methoxy-, and 2 - ( 2, 6-dimethylpheny 1) -6-methoxy-1 , 2 , 3 4- tetrahydro-l-naphthalenone, there are obtained l-(p-hydroxyphenyl) -2-phenyl-6-ethoxy-, 1-(p-hydroxypheny1) -2-phenyl-6-penty1oxy-, 1-(p-hydroxyphenyl) - -phenyl-6-hexyloxy-, l-(p-hydroxyphenyl) -2-phenyl-6-isooctyloxy-, l-(p-hydroxyphenyl) -2-(2-bromophenyl) -6-methoxy-, l-(p-hydroxyphehyl) -2-(3-chlorophenyl) -6-methoxy-, l-(p-hydroxyphenyl) -2-(2-chloro-6-fluorophenyl) - 6-methoxy-, l-(p-hydroxyphenyl) -2-(2,3-dlchlorophenyl) -6-methoxy-., l-(p-hydroxyphenyl) -2-(p-tolyl) -6-methoxy-, and 1-(p-hydroxyphenyl) -2-(2,6-dimethylphenyl) -6-methoxy- 3, -dihydronaphthalene, respectively.

The corresponding l-(o-hydroxyphenyl) - and l-(m-hydroxypheny 2-substituted-6-substituted-3, -dihydronaphthalenes are obtained by employing o-bromophenyl tetrahydropyranyl ether and m-bromophenyl tetrahydropyranyl ether, respectively, in place of p-bromophenyl tetrahydropyranyl ether in the procedure of Preparation 7.

Preparation 8 l-(p-fluorophenyl) -2-phenyl-6- methoxy-5, -dihydronaphthalene Using the procedure described in Preparation 6, but replacing bromobenzene by p-bromofluorobenzene, there was obtained l-(p-fluorophenyl) - -phenyl-6-methoxy-3, -dihydronaphthalene in the form of a crystalline solid having a o melting point of 99 to 101 C. I Similarly other l-(halophenyl) -2-phenyl-6-alkoxy-3,4-dihydronaphthalenes are obtained by reacting the appropriate halophenylmagnesium halide with the appropriate 2-phenyl-6-alkoxy-l,2,3,4-tetrahydro-l-naphthalenone using the procedure described in Preparation 6.

Preparation 9 l-(p-tolyl) -2-phenyl-6-methoxy 3, 4-dihydronaphthalene Using the procedure described in Preparation 6, but replacing bromobenzene by p-bromotoluene, there was obtained l-(p-tolyl) -2^phenyl-6-methoxy -3, 4-dihydronaphthalene in the o form of a crystalline solid having a melting point of 100 to 103 C.

Similarly, other l-(alkylphenyl) -2-phenyl-6-alkoxy-3, 4-dihydronaphthalenes are obtained by reacting the appropriate alkylphenylmagnesium halide with the appropriate 2-phenyl-6-alkoxy-l, 2, 3, 4-tetrahydro-l-naphthalenone using the procedure described in Preparation 6.

Example 1 1, 2 -dlphenyl-6-methoxy-l, 2, 3, 4-tetrahydronaphthalene A solution of 0.63. g. of l, 2-diphenyl-6-methoxy-3, 4-dihydronaphthalene in 20 ml. of tetrahydrofuran and 1 ml. of tert.butyl alcohol was added to 100 ml. of ammonia redistilled from lithium. To this there was added 28 mg. of lithium wire; the color faded very quickly. After to 10 minutes an additional 28 mg. of lithium were added. The blue color this time prevailed for 20 minutes. After the addition of 1 g. of solid ammonium chloride, the mixture was taken to dryness under a stream of nitrogen. The residue was then washed with ether and methylene chloride . The solid which remained when the extracts were taken to dryness was recrystallized from ethanol. There was thus obtained 0.53 g. of 1, 2-diphenyl-6-methoxy-l, 2, 3, 4- o tetrahydronaphthalene. having ;,a melting point of 160 to 162 C.

One further crystallization from the same solvent gave an o analytical sample, m.p. 166 to 168 C.

Anal. Calcd. for C23H220 : C, 87 .86 ; H, 7 .05 Found: C, 87 -30; H, 7 - 15.

Example 2 l-(p-hydroxyphenyl) -2-phenyl-6-methoxy- 1, 2, 5, -tetrahydronaphthalene One gram of l-(p-hydroxyphenyl) -2-phenyl-6-methoxy-3, -dlhydronaphthalene was reduced by means of 84 mg. of lithium in exactly the same manner as described in Example 1. The gummy solid which remained when the solvents had been removed from the reaction mixture was suspended in water and the suspension was acidified with acetic acid. The solid was collected on a filter and recrystalllzed twice from methanol to yield 0.40 g. of l-(p-hydroxyphenyl) -2-phenyl-6-methoxy-1,2,3, -tetrahydronaphthalene, having a melting point of 188 to 190°C.

Anal. Calcd. for C23H22O2: C, 83.60; H, β.γΐ Pound: ; C, 85.4-5; H, 6.89.

Example 3 l-[p-(2-pyrrolidinoethoxy)phenyl] -2-phenyl-6-methoxy 1,2,3, -tetrahydronaphthalene and the hydrochloride thereof To a solution of 2.0 g. of l-(p-hydroxyphenyl) -2-phenyl-6-methoxy-l,2,3, -tetrahydronaphthalene in 10 ml. of dimethyl-formamide and 50 ml. of benzene there was added 275 mg. of sodium hydride (53# in mineral oil). When effervescence had ceased (10 minutes), i.65 g. of a 1:1 mixture of 2-pyrrolidinoethyl chloride and toluene was added to the solution. The mixture was heated under reflux for 17 hours, allowed to cool and diluted with ether. This mixture was washed with water and saturated sodium chloride solution and distilled the organic layer was-fcaleeft to dryness. The residue was dissolved in ether and this. solution was extracted with five-50-ml. portions of 2.5 N hydrochloric acid. The acid extracts were in turn extracted with methylene chloride. The solid which remained when the methylene chloride extract was taken to dryness was recrystallized twice from ai mixture of methylene chloride and ethyl acetate. There was thus obtained 2 .25 g. of 1-[p-( 2-py rolidinoethoxy)pheny 1 ] -2-phenyl -6-methoxy— 1 , 2, 5, 4-tetrahydronaphthalene hydrochloride in the form of a crystalline o solid having a melting point of 211 to 215 C.

Anal. Calcd. for C29H3 CINO2 : C, 75 - 06 ; H, 7 -59 ; CI, 7 .64 Found: C, 7^ .85J H, 7 .61; CI, 7 -72. 1 g. of the hydrochloride so obtained is dissolved in methylene chloride and the solution so obtained is washed with aqueous sodium bicarbonate solution. The washed methylene chloride solution is evaporated to dryness to yield l-[p-( 2-pyrrolidinoethoxy)phenyl] -2-phenyl-6-methoxy-l, 2, , 4-tetrahydronaphthalene , Using the above procedure but replacing 2-pyrrolidinoethyl chloride by 2-diethylamlnoethyl chloride, 5-dimethylamlnopropyl chloride, 5-diethylaminobutyl chloride, 5-dlmethylaminopentyl bromide, 6-dimethylaminohexyl chloride, -( 2, 2-dimethylpyrrolidino)propyl bromide, 2-piperidinoethyl chloride, 2-morpholinobutyl bromide, l-methyl-4-(2-chloroethyl) -piperazine, 2-hexamethyleniminoethyl chloride, 2-homopiperazinoeth l chloride and 2-homomorpholinoethyl chloride, there are obtained l-p-( 2-diethylaminoethoxy)phenyl-, l-p-( 5-dimethylaminopropoxy)phenyl-, l-p-( 5-diethylaminobutoxy) -phenyl-, l-p-( 5-dimethylamlnopentyloxy)phenyl-, 1-p-( 6-dimethylaminohexylox )phenyl-, I-jp-[ 5 - ( 2 , 2 -dimethylpyrrolidino)propoxy]phenyl^ l-[p-( 2-piperidinoethoxy) -phenyl]-, 1-[p-( 2-morpholinobutoxy)phenyl] -, l- p-[2-( 1-methyl-4-piperazino) ethoxy]phenylj--, 1-[p-( 2-hexamethyleniminoethoxy) -, phenyl]-, l-[p-( 2-homopiperazinoethoxy)phenyl] - and l-[p-(2- - - - - - - s Example 4 Ethyl 2-[p-( 6-methoxy-2-phenyl-l,2,3, 4- tetrahydro-l-naphthy 1)phenoxy] -2-methylproplonate To a solution of 2.5 g. of l-(p-hydroxyphenyl) -6-methoxy-2-phenyl-l,2, 3, 4-tetrahydronaphthalene in 15 ml. of dimethylformamide and 6 ml. of benzene, is added wi†;h stirring Ο.35 g. of sodium hydride as a 53$ suspension in mineral oil. When the effervescence has subsided the solution is treated with a solution of 1.5 g. of ethyl 2-bromo-2-methylpropionate in 1 ml. of benzene and the mixture is heated under reflux for 17 hours. The resulting mixture is allowed to cool, washed with water and with saturated sodium chloride solution, and the organic layer is evaporated tocdryness. The residue is chromatographed on a column of magnesium silicate ( Plorisil) and the column is eluted with petroleum ether containing increasing proportions of acetone. Those fractions which, on the basis of infrared absopption analysis are found to contain the desired product, are combined andeevaporated to dryness.

The residue is recrystallized from petroleum ether to yield ethyl 2-[p-( 6-methoxy-2-phenyl-l,2, 3,4-tetrahydro-l- ? naphthyl)phenoxy] -2-meth lpropionate in the form of a crystalline solid.

Similarly, using the above procedure but replacing ethyl 2-bromo-2-methylpropionate by ethyl bromoacetate, ethyl 5-bromovalerate and methyl 9-bromocaprate, there are obtained ethyl p-( 6-methoxy-2-phenyl-l,2, 3,4-tetrahydro-l-naphthyl)phenoxyacetate, ethyl 5-[p-( 6-methoxy-2-phenyl-l,2, 3,4-tetrahydro-l-naphthyl)phenoxy] alerate and methyl 9-[p-( 6-methoxy-2-phenyl-l,2,5,4-tetrahydro-l-naphthyl)phenoxy]caprate, respectively.

Example 5 2-[p-( 6-methoxy-2-phenyl-l,2, 3,4-tetrahydro- 1-naphthyl)phenoxy] -2-methylpropionic acid (prepared as described in Example 4) and 3 ml. of 50$ aqueous potassium hydroxide in 50 ml. of methanol is heated under reflux for 5 hours. The reaction mixture is then evaporated to dryness and the residue is suspended in water and made strongly acid by the addition of 2.5 N hydrochloric acid.

The solid which separates is isolated by filtration and recrystallized twice from aqueous methanol. There is thus obtained 2-[p-( 6-methoxy-2-phenyl-l, 2,3, 4-tetrahydro-l-naphthyl)phenoxy] -2-methylpropionic acid in the form of a crystalline solid.

Using the same procedure, p-( 6-methoxy-2-phenyl-l, 2, 3, 4-tetrahydro-l-naphthyl)phenoxyacetic acid, 5-[p-( 6-methoxy-2-phenyl-l, 2, 3, 4-tetrahydro-l-naphthyl)phenoxy]valeric acid, and 9-[p-( 6-methoxy - -phenyl -1 , 2 , 3 , 4-feetrahydro -1-naphthy 1)phenoxy] -capric acid, respectively, are obtained from the corresponding ethyl and methyl esters (prepared as described in Example 4) .

Example 6 1-[p-( 2, -dihydroxypropoxy)phenyl] -2-phenyl- 6-methoxy-l, 2, 3, -tetrahydronaphthalene To a suspension of 2 .97 g. of l-(p-hydroxyphenyl) -2-phenyl -6-methoxy-l, 2, 3, 4-tetrahydronaphthalene in 50 ml. of methanol is added 2 .1 ml. of 4 .55 N sodium methoxide in methanol. When the solid has all dissolved, 1.0" g. of 3-chioro-l, 2 -propanediol is added to the mixture and the latter is then heated for 20 hours under reflux. The resulting mixture is evaporated to dryness under reduced pressure and the residue is dissolved in a mixture of ether and water. The organic layer is separated, washed successively with aqujsous sodium hydroxide solution, water, and saturated sodium chloride solution before being evaporated to dryness. The residue is chromato-graphed on a column of magnesium silicate (Florisil) and the File 13108 22.11.66 column is eluted with petroleum ether containing increasing proportions of acetone. Those fractions which, on the basis of infrared and papergram analyses, are found to contain the desired material are combined and evaporated to dryness. The residue is «^^ρ·1·0111 τΐλΐΐ recrystallized from aqueous methanol to obtain l- p-(2,5-dihydroxypropoxy) henyl] ~2-phenyl-6-methoxy-l,2,3»4-tetrahydronaphthalene, M.P. (after recrystallization from diethyl ether and commercial hexane) :126-128°C.

Using the above procedure, but replacing 3-chloro- 1.2-propanediol by l-chloro-2,3-butanediol and 5-bromo- 1.3-pentanediol, -bu oxy)pbenyl| -an phen l-6-me hoxy-l,2,3»4-tetrahydronaphthalene,respectivel .

EXAMPLE 7i 1- p-(2,3-epoxypropox ) henyl^-2-phenyl-6-methoxy— 1,2,3*4-tet ahydronaphthalene Using the procedure described in Example 4, but replacing ethyl 2-bromo-2-methylpropionate by eplchlorohydrin, there is obtained 1-jj?-(2, -epoxypropoxy)phenylj -2-phenyl-6-methoxy-l,2,3»4-tetrahydronaphthalene· Similarly, using the procedure of Example 4, but replacing hyl 2-bromo-2-methylproplonate ¾y 3-bromo-1,2-epoxybutane(Chemical Abstracts 36,404,1942) and -bromo-a,2-epoxypentane ( i is¾nj.chem. Soc.1945,48) , there are obtained (2, 3-epoxy-l-methylpropox )pheny^ - %oi& i ?repoxyjpen tyloxy)piaenyl -2-phenyl-6-methoxy-l,2,3*4* V P.A.23284 File 13108 22.11.66 EXAMPLE 8i 1-\j>-(3-aiaino-2-hydroxypropoxy)pheny- -2- phenyl-6-methoxy-l, 2, 3»4- etrahydronap thalene and the hydrochloride thereof A mixture of 3-0 g. of l~ p-(2, 3-epoxypropoxy)phenyl| -2 phenyl-6-methoxy-l»2,3t4- etrahydronaphthalene,0.80 g. of succinimide and 4 drops of pxperidine in 100 ml. of absolute ethanol Is heated under reflux for 17 hours. The resulting mixture is concentrated to approximately one-third volume by distillation under reduced pressure and the residue is diluted with water. The mixture so obtained is extracted with methylene chloride and the methylene chloride extract is washed with water and saturated sodium chloride solution before being evaporated to dryness. The residue is recrystallized from aqueous alcohol to; yield l-[p-(3-succlnimido-2-hydroxypropoxy)phenyl] -2-pheny1-6-methoxy-1,2,3, -tetrahydro-naphthalene. The latter compound is then heated under reflux for 20 hours with a solution of l6 g. of sodium hydroxide in 320 ml. of ethanol. The resulting product is concentrated by distillation under reduced pressure and the residue is extracted with a mixture of methylene chloride and water. The methylene chloride solution is separated, washed with water, and then shaken with 100 ml. of 2.5 N hydrochloric acid. The solid which separates is isolated by filtration, washed with methylene chloride, and dried. There is thus obtained l-[p-(3-amino-2-hydroxypropoxy)phenyl]-2-phenyl-6-methoxy-1, 2,3,4-tetrahydronaphthalene hydrochloride. The corresponding free base is obtained by dissolving the hydrochloride in methylene chloride, washing the resulting solution with aqueous sodium bicarbonate solution, and evaporating the methylene chloride solution to dryness .

Using the above procedure, but replacing l-[p-(2,3-epoxypropoxy)phenyl] - -phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene by l-[p-(2, 3-epoxy-l-methylpropoxy)phenyl] and l-[p-(4, 5-epoxypentyloxy)phenyl] -2-phenyl-6-methoxy-1,2,3, 4-tetrahydronaphthalene, there are obtained l-[p-(3-amino-2-hydroxy-1-methylpropoxy)phenyl] - and l-[p-( 5-amino-4-hydroxypentyloxy)phenyl] -2-phenyl-6-methoxy-l,2,3, 4-tetrahydro- Example 9 5- [p-( 6-methoxy -2-phenyl -1, 2, 3, -tetrahydro -1 - naphthyl)phenoxy]methylJ -2-oxazolidinethione A solution of 2.8 g. of l-[p-( 3-amino-2 -hydroxypropoxy) pheny 2-phenyl-6-methoxy-l, 2, 3, 4-tetrahydronaphthalene in 100 ml. of ethanol:is mixed with Ο.85 ml. of carbon disulfide and 3.1 ml. of 25$ aqueous potassium hydroxide solution. The resulting mixture is heated under reflux for 4 hours and then concentrated under reduced pressure. The concentrate is suspended in water and the suspension acidified with 2 .5 N hydrochloric acid. The suspension is extracted with hot methylene chloride and the methylene chloride extract is evaporated to dryness. There is thus obtained 5-{[p-( 6-methoxy-2-phenyl-l, 2, 3, 4-tetrahydro-l-naphthyl)phenoxy]methyl} -2-oxazolidinethione .

Using the above procedure but replacing 1-[p-( 3-amino÷ -hydroxypropoxy) phenyl ] -2-phenyl -6-methoxy-l, 2, 3, 4-tetrahydronaphthalene by l-[p-( 2, 3-epoxy-l-methylpropoxy)phenyl] -and 1-[ p-( 4, 5-epoxypentyloxyj phenyl] - -phenyl -6-methoxy-1 , 2, 3,4-tetrahydronaphthalene, there are obtained 5- l-[p-( 6-methoxy-2-phenyl-1, 2, 3* 4-tetrahydro-l-naphthyl)phenoxy]ethyl) - and Example 10 5-{[p-( 6-methoxy -2-phenyl -1, 2, 3, 4-tetrahydro -1 - naphthyl) phenoxy]methyl} -2-oxazolidinone To a vigorously stirred suspension of 3.7 g« of l-[p-( 3-amino-2 -hydroxypropoxy) phenyl ] -2-phenyl -6-methoxy-l, 2, 3, 4-tetrahydronaphthalene in 30 ml. of toluene and 30 ml. of 12 .5$ aqueous potassium hydroxide solution is added dropwise over a short period 3 ·2 g. of phosgene in 10 ml. of toluene. The solid which separates is isolated by filtration and dissolved in methylene chloride . The methylene chloride solution is extracted with dilute hydrochloric acid before being evaporated to dryness. There is thus obtained 5- [p-(6-methoxy-2-phenyl-1, 2,5, -tetrahydro-l-naphthyl)phenoxy]methyi--2-oxazolidinone .

Using the above procedure but replacing l-[p-(5-amino-2-hydroxypropoxy) phenyl ] -2-phenyl-6-methoxy-l, ,5> 4-tetrahydronaphthalene by 1-[p-( ,5-epoxy*l-methylpropoxy) phenyl 1-and l-[p-(4, 5-epoxypentyloxy) phenyl]-2-phenyl-6-methoxy-1,2,5, -tetrahydronaphthalene, there are obtained 5- l-[p-(6-methoxy-2-phenyl-1,2,5, 4-tetrahydro-1-naphth 1) henoxy]ethyl^-and 5-fj- [p-(6-methoxy-2-phenyl-1,2,5,4-tetrahydro-1- Example 11 1-( p-methoxyphepy1) -2-phenyl-6-meihoxy- 1,2,5t 4-tetrahydronaphthalene Using the procedure described in Example ξ, but- replacing 5-chloro-l,2-propanediol by methyl iodide and reducing the reaction time to 2 hours, there is obtained l-(p-methoxyphenyl) -2-pheny1-6-methoxy-1,2, 5, -tetrahydronaphthalene , Example 12 l-(p-tolyl) -2-phenyl-6-methoxy- lj2j y4-tetrahydronaphthalene Using the procedure described in Example 1, but replacing l,2-diphenyl-5,4-dihydronaphthalene by l-(p-tolyl) -2-phenyl-6-methoxy-5,4-dihydronaphthalene, there is obtained l-(p-tolyl) -2-phenyl-6-methoxy-l,2,5 4-tetrahydronaphthalene .

Similarly, using the procedure described in Example 1, but replacing l,2-dlphenyl-5,4-dihydronaphthalene by l-(p-hydroxyphenyl) -2-phenyl-6-ethoxy-, l-(prhydroxyphenyl) -2-phenyl-6-pentyloxy-, 1-( p-hydroxyphenyl) -2-phenyl-6-hexylox -, l-(p-hydroxyphenyl) -2-phenyl-6-iso*oct loxy-, l-(p-hydroxyphenyl) -2-(2-bromophenyl) -6-methoxy-, l-(p-hydroxy-phenyl) -2-(3-chlorophenyl) -6-methoxy-, l-(p-hydroxyphenyl) -2-(2-chloro-6-fluorophenyl) - 6-methoxy-, l-(p-hydroxyphenyl) -2-(2,3-dichlorophenyl) -6-methoxy-, l-(p-hydroxyphenyl) -2-(p-tolyl) -6-methoxy-, l-(p-hydroxyphenyl) -2-(2,6-dimethylphenyl) -6-methoxy-, 1,2-dipheny1-6-ethoxy-, 1,2-dipheny1-6-penty1oxy-, 1, 2-dlphenyl-6-hexyloxy-, l,2-diphenyl-6-iso6*ctyloxy-, lrphenyl-2-(2-bromophenyl) -6-methoxy-, 1-phenyl-2-(3-chloropheny1) -6-methoxy-, l-phenyl-2-(2-chloro-6-fluorophenyl) -6-methoxy-, 1-phenyl-2-(p-toly1) -6-methoxy-, l-phenyl-2-(2,6-dlmethylphenyl) -6-methoxy-, and l-(p-fluorophenyl) -2-phenyl-6-methox -3, 4- dihydronaphthalenes, there are obtained the corresponding 1,-2,3, 4-tetrahydronaphthalen The l-(hydroxyphenyl) -1,2,3, -tetrahydronaphthalenes so obtained are converted to the corresponding 1 l-( tertiaryaminoalkoxyphenyl) -, l-( alkoxyphenyl) -, l-(carbalkoxyalkoxyphenyl) -, l-( carboxyalkoxyphenyl) -, l-( epoxyalkoxyphenyl) -, 1^[ (^-amino-l-hydroxyethyl) alkoxyphenyl] -1-f[5-(2-oxooxazolidinyl) ]alkoxyphenyl}^, l-^[5-(2-thioxoo azolidinyl) ]alkoxyphenyl--, and l-(dihydroxyalkoxyphenyl) derivatives thereof using the procedures set forth in Examples 3 through 11, above.

Example 13 lj2-diphenyl-6-methoxy-l,2,3,4>5,8- hexahydronaphthalene A solution of 0.31 g. of l,2-diphenyl-6-methoxy-l,2,3, 4-tetrahydronaphthalene in 10 ml. of tetrahydrofuran and 1 ml. of tert.butyl alcohol was added to 50 ml. of liquid ammonia redistilled from lithium. Lithium wire ( 0.07 g.) was added in 7 equal portions to the mixture at 5-minute intervals .

The resulting mixture was stirred for 30 minutes before 3 ml. of tert .butyl alcohol was added. Following an additional minutes stirring, there was added 0.3 g. of ammonium chloride , The solvent was evaporated from the mixture under a stream of nitrogen and the residue was treated with water.

The solid was collected on a filter and recrystallized from ligroin to afford l, 2-diphenyl-6-methoxy-l, 2, 3, 4, 5, 8- o hexahydronaphthalene having a melting point of 132 to 134 C.

Anal. Calcd. for C23H2 0: C, 87 . 0; H, 7 .65 Found: C, 87 .02 ; H, 7 -90.

Example 14 l-(p-hydroxyphenyl) -2-phenyl-6-methoxy- 1, 2,3, > 5, 8-hexahydronaphthalene Using the procedure described in Example 13, 0.66 g. of 1-( p-hydroxyphenyl) -2-phenyl -6-methoxy-1 , 2 , 3 , 4-tetrahydronaphthal was reduced with 154 mg. of lithium. The reaction mixture was worked up as in Example 1 and the product was recrystallized fro aqueous methanol. There was obtained 0.55 8 · of l-(p-hydroxyphenyl) -2-phenyl-6-methoxy-l, 2, 3, , 5>8- o hexahydronaphthalene having a melting point of 184 , 5 to 187 .5 C.

An analytical sample prepared by further recrystallizatlon o from the same solvent melted at 183 to 185 C.

Anal, Calcd. for CaaHa^a: C, 83.10; H, 7 .28 Found: C, 83 .07 ; H, 7.40.

Using the procedure described in Example 13, but replacing l, 2-diphenyl-6-methoxy-l, 2, 3i -tetrahydronaphthalene by the appropriately substituted l, 2-diphenyl-6-alkoxy-l, 2, 3, 4-tetrahydronaphthalene is productive of the corresponding 1,2,3* , 5*8-hexahydronaphthalene. Representative of the latter compounds so prepared are 1-(p-hydroxyphenyl -2-phenyl-6-ethoxy-, 1-(p-hydroxyphenyl -2-phenyl-6-pentyloxy-, l-(p-hydroxyphenyl -2-phenyl-6-hexyloxy 1-(p-hydroxyphehy1 -2-phenyl-6-isoOctyloxy-, 1-(p-hydroxyphenyl -2-(2 bromophenyl) -6-methoxy^, 1-(p-hydroxyphenyl -2-(3-chloropheriyl) -6-methoxy-, 1-(p-hydroxyphenyl -2-(2-chloro-6-fluorophenyl) -6-methoxy l-(p-hydroxyphenyl -2-(2, 3-dic.hlorophehyl) -6-methoxy-, 1-(p-hydroxypheny1 -2-(p-tolyl) -6-methoxy-, 1-(p-hydroxyphenyl -2-(2,6-dimethylphenyl) -6-methoxy-, 1,2-dlpheny1-6-ethoxy-, 1, 2-diphenyl-6-pentyloxy-, l,2-diphenyl-6-hexyloxy-, l,2-diphenyl-6-isooctyloxy-, l-phenyl-2-( 2-rbromophenyl) -6-methoxy-, 1-phenyl-2-(3-chlorophenyl) - -methoxy-, 1-phenyl-2-(2-chloro-6-fluorophenyl) -6-methoxy-, 1-phenyl-2-(p-tolyl) -6-methoxy-, ; 1-phenyl-2-(2,6-dirhethylphenyl) -6-methoxy-, and 1-(p-fluorophenyl) -2-phenyl-6-methoxy-1,2,3» * 5*8- hexahydronaphthalene:.

The above compounds which contain a l-(hydroxyphenyl) substituent can be etherified according to the procedures set forth in Examples 3 through 11 to produce the corresponding l-( alkoxyphenyl) -, l-( tertlaryaminoalkoxyphenyl) -, l-( carbalkoxyalkoxyphenyl) -, l-( carboxyalkoxyphenyl) -, l-(epoxyalkoxyphenyl) -, l-[(2-amlno-l-hydroxyethyl)alkoxyphenyl] -l-([5-(2-oxob'xazolidinyl) ]alkoxyphenyl} -, l- [5-(2-thioxooxazolidinyl) ]alkoxyphenyl -, and :.■ Example 15 5, 6-diphenyl-3,4, 5, 6,7,8- hexahydro-2( 1H) -naphthalenone A suspension of 2.0 g. of l,2-diphenyl-6-methoxy-l,2,3,4, 5,8- hexahydronaph halene in 400 ml. of methanol and 20 ml. of 2.5 N hydrochloric acid was stirred for 20 minutes in an ice bath and o 1 hour at room temperature (about 25 C) . The now homogeneous solution was neutralized with saturated aqueous sodium bicarbonate solution and the bulk of the solvent was removed on a rotary evaporator. Ether was added to the residue and the organic layer was washed with water and saturated sodium chloride solution before being evaporated to dryness. The residual gum was recrystallized 3 times from a small amount of ligroin to give 0.82 g. of 5, 6-diphenyl-3,4, 5, 6,7, 8-hexahydro-2(lH)- . o naphthalenone having a melting point of 124 to 129 C. o An analytical sample, melting point 128 to 132 C, was obtained by recrystallization from ligroin of the product from another run.

Anal. Calcd. for C22H220: C, 87 .37J H, 7 - 33 Found: C, 87 ·77 J H, 7- 2, Example 16 5-(p-hydroxypheny¾-6-phenyi-3, , 5, 6,7,8- hexahydro-2( 1H) -naphthalenenone A suspension of 1.65 g. of l-(p-hydroxyphenyl) -2-phenyl-6-methoxy-l,2, 3,4, 5, 8-hexahydronaphthalene in 83 τα1% of methanol containing 3 „3· ml. of 1 M methanolic oxalic acid was stirred at o room temperature (about 25 C.) until the material was all in solution (40 minutes). The solution was then taken to dryness at reduced pressure and the residue was dissolved in a mixture of ether and methylene chloride. This solution was washed in turn with water, aqueous sodium bicarbonate solution, and saturated sodium chloride solution. The residue which remained when the solvent was removed from the organic layer was recrystallized from methanol. There was obtained first crop of 0.53 g. of 5-(p-hydroxyphenyl) -6-phenyl-3,4, 5,6,7,8-hexahydro-2(lH) -naphthalenone having a melting point of 209 to o 216 C; the second crop of material was recrystallized from aqueous methanol to give an additional 0.90 g. of the same compound having a melting point of 213 to 2l6°E, The analytical sample, obtained b recrystallization of o the first crop from methanol,: melted at 215 to 224 C.

Anal. Calcd. for C2aHa202: C, 82.98; H, 6.96 Found: C, 82.72; H, 7.28.

Using the procedure described in Example 15, but replacing 1, 2-diphenyl-6-methoxy-l, 2,3,4, 5,8-hexahydronaphthalene by the 1,2,3> ,5,8-hexahydronaphthalenes disclosed immediately after Example 14, there are produced the following 3,4, 5,6,7,8-hexahydro-2 ( 1H) -naphthalenones : -(p-hydroxyphenyl) -6-phenyl-, -(p-hydroxyphenyl) -6-(2-bromophenyl) -, -(p-hydroxyphenyl) -6-{3-chlorophenyl) -, -(p-hydroxyphenyl) -6-(2-chloro-6-fluorophenyl) -(p-hydroxyphenyl) -6-(2,3-dichlorophenyl) -, -(p-hydroxyphenyl) -6-(p-tolyl) -, -(p-hydroxyphenyl) -6-(2, 6-dimethylphenyl) -, ,6-dlphenyl-, -phenyl-6-(2-bromophenyl) -, -phenyl-6-(3-chlorophenyl) -, -phenyl-6-(2-chloro-6-fluorophenyl) -phenyl-6-(p-tolyl) -, -phenyl-6-(2,6-dimethylpheny1 -, and -(p-fluorophenyl) -6-phen y1-3, 4, 5, 6,7,8-hexahydro· 2 1H -na hthalenone .

The above compounds which contain a 5-(hydroxyphenyl) substituent can be etherified according to the procedures set forth in Examples 3 through 11 to produce the corresponding 5-(alkoxyphenyl) -, 5-( tertiaryaminoalkoxyphenyl) -, -( carbalkoxyalkoxyphenyl) -, 5-( carboxyalkoxyphenyl) -, -(epoxyalkoxyphenyl) -, 5-t(2-amino-l-hydroxyethyl) alkoxyphenyl] 2( 3H) -naphthalenone A solution of 1 g. of 5, 6-diphenyl-3,4, 5,6,7,8-hexahydro-2( 1H) -naphthalenone in 20 ml. of ethanol and 5 ml. of concentrat hydrochloric acid is heated under reflux for 5 hours. At the en of this time the reaction mixture is evaporated to dryness and the residue is dissolved in methylene chloride and chromatograph on a column of magnesium silicate (Plorisil). The column is eluted with petroleum ether containing increasing proportions of acetone and those fractions which, oh the basis of infrared spectral analysis are found to contain the desired material, are combined and evaporated to dryness. There is thus obtained 5,6-diphenyl-4,4a, 5,6,7,8-hexahydro-2(3H) -naphthalenone .

Using the above procedure, but replacing 5>6-diphenyl-J>» 5> 6,7,8-hexahydro-2( lH) -naphthalenone by 5-(p-hydroxyphenyl) 6-phenyl-3, , 5, 6,7,8-hexahydro-2( 1H) -naphthalenone, there is obtained 5-(p-hydroxyphenyl) -6-phenyl-4, 4a, 5> 6,7,8-hexahydro-2(3H) -naphthalenone .

Similarly, using the procedure of Example 17, but replacing 5, 6-diphenyl-3, 4, 5, 6,7,8-hexahydro-2(lH) -naphthalenone by the 3i4,5,6,7,8-hexahydro-2(lH)-naphthalenones disclosed immediately after Example ΐβ, there are produced the corresponding 4, 4a, 5, 6,7, 8-hexahydro-2( 3H)-naphthalenoneB as follows: -(p-hydroxyphenyl) -6-phenyl-> -(p-hydroxyphenyl) -6-( 2-bromophenyl) -, -(p-hydroxyphenyl) -6-( 3-chlorophenylj -(p-hydroxyphenyl) -6-t( 2-chloro-6-fluorophenyl) -, -(p-hydroxyphenyl) -6-( 2, 3-dichlorophenyl) -, -(p-hydroxyphenyl) -6-(p-tolyl) -, -(p-hydroxypheny3)-6-( 2, 6-dimethylphenyl) , 6-diphenyl-, -phenyl-6-( 2-bromophenyl) -, -phenyl-6-(3-chlorophenyl) -phenyl-6-( 2-chloro-6-fluorophenyl) -, -phenyl-6-(p-tolyl) -, -phenyl-6-(2, 6-dimethylphenyl) and -(p-fluorophenyl) -6-phenyl- . 4, a, 5, 6,7,8-hexahydro-2(3H) -naphthalenone .

The above compounds which contain a 5-(hydroxyphenyl) substituent can be etherifled according to the procedures set forth in Examples 3 through 11 to produce the corresponding -( alkoxyphenyl) 5-( tertiaryaminoalkoxyphenyl,) -( carbalkoxyalkoxyphenyl) -, 5-( carboxyalkoxyphenyl) -, -(dihydroxyalkoxyphenyl) - derivatives thereof.

Example 18 l-[p-( 2-pyrrolidinoethoxy)phenyl] -2-phenyl- 6-methoxy-l, 2, 3, , 5* 8-hexahydronaphthalene and the hydrochloride: thereof Using the procedure described in Example 3, but replacing 1- -h drox hen l -2- hen l -6-methox -1 , 2 , 3, 4-tetrah dronaphthale by l-(p-hydroxyphenyl) -2-phenyl-6-methoxy-l,2,3, 4, 5,8-hexahydronaphthalene, there are obtained l-[p-(2-pyrrolidinoe hoxy)phenyl] - -phenyl-6-methoxy-l,2, 3, , 5,8-hexahydronaphthalene and the hydrochloride thereof.

Similarly, using the procedure described in Example 3, but replacing l-(p-hydroxyphenyl) -2-phenyl-6-methoxy-l,2,3, 4-tetrahydronaphthalene by 5-(p-hydroxyphenyl) -6-phenyl-3 , 4, 5, 6,7,8 hexahydro-2(lH) -naphthalenone and 5-(p-hydroxyphenyl) -6-phenyl-4, 4a, 5, 6,7,8-hexahydro-2(3H)-naphthalenone, there are obtained 5-[p-(2-pyrrolidinoethoxy)phenyl] -6-phenyl -3, 4, 5, 6,7,8-hexahydro-2( 1H) -naphthalenone and 5-[p-(2-pyrrolidinoethoxy)phenyl) ] -6-phenyl-4, 4a, 5, 6,7,8-hexahydro-2(3H) -naphthalenone, respectively, and the hydrochlorides thereof.

Example 19 1-[p-(2-pyrrolidinoethoxy)phenyl] -2-phenyl- 6-methoxy-l,2, , 4-tetrahydronaphthalene hyd obromide To a solution of 1 g. of 1-[p-(2-pyrrolidinoethoxy)phenyl] -2-phenyl-6-methoxy-l,2, 3, 4-tetrahydronaphthalene in 100 ml. of ether is added dropwise, with stirring, a slight excess of a 0,1 N ethereal solution of hydrogen bromide. The solid which separates is isolated by filtration, washed with ether,, and dried. There is thus obtained l-[p-(2-pyrrolidinoethoxy)phenyl] -2-phenyl -6-methoxy-l,2, , 4-tetrahydronaphthalene hydrobromide .

In like manner, employing any of the free amino compounds set forth in Examples 3, 8, 12, 14, 36, 17 and 18 and the appropriate acid, there are obtained the corresponding acid addition salts. Illustratively, using the procedures analogous to those described above, the amines of Examples 3, 8, 12, 14, 16, 17 and 18 are converted to their acid addition salts with sulfuric, nitric, phosphoric, lactic, benzoic, methanesulfonic, p-toluenesulfonic, salicylic, acetic, propionic, malic, tartaric, citric, cyclohexanesulfamic, succinic, nicotinic, and ascorbic acids. Example 20 1-[p-(2-pyrrolidinoethoxy) phenyl ] -2-phenyl- 6-methoxy-1,2, , -tetrahydronaphthalene methiodide A solution of 1 g. of l-(p-(2-pyrrolidinoethoxy)phenyl] -2-phenyl-6-methoxy-l,2, , -tetrahydronaphthalene in 12 ml. of acetonitrile is cooled in ice. To the cooled solution is added 1.5 ml. of methyl iodide and the mixture is allowed to stand overnight before being poured into 100 ml. of ether. The solid which separates is Isolated by filtration and recrystallized from a mixture of acetonitrile and ether. There is thus obtained 1- [p-( -pyrrolidinoethoxy) phenyl]- -phenyl-6-me thoxy-l, 2,3,4-tetrahydronaphthalene methiodide in the form of a crystalline solid.

Similarly, using the above procedure, but replacing methyl iodide by ethyl bromide, propyl bromide, ally! bromide, and benzyl bromide, there are obtained the ethobromide, propyl bromide, allyl bromide, and benzyl bromide, respectively, of 1-[p-(2-pyrrolidinoeth035r)phenyl3-2-phenyl-6-methoxy-l,2,3, 4-tetrahydronaphthalene .

Similarly, using the procedure described in Example 20, but replacing 1- [p-(2-pyrrolidinoethoxy)phenyl ] -2-phenyl-6-methoxy-1,2, 3, 4-tetrahydronaphthalene by any of the tertiary bases prepared as described in Examples 3, 8, 12, 14, 16, 17 and 18, there are obtained the corresponding methiodides and like quaternary ammonium salts.

Example 21 1-[p-(2-pyrrolidinoethoxy)phenyl] -2-phenyl-6- methoxy-1, 2, 3, 4-tetrahydronaphthalene meth.ochloride A solution of 1 g. of l-[p-(2-pyrrolidinoethoxy)phenyl] -2- - - - - dimethylformamide is shaken with a suspension of silver oxide until the precipitation of silver oxide is complete. The resulting mixture is filtered and the filtrate containing the ; corresponding quaternary ammonium hydroxide is neutralized by the addition of aqueous hydrochloric acid. The resulting mixture is evaporated to dryness to obtain l-[p-(2-pyrrolldinoethoxy)phenyl]-2rphen l-6-methoxy-l,2,5» -tetrahydronaphthalene methochloride .

Similarly, using the above procedure, but replacing hydrochloric acid by other acids such as sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, methanesulfonic acid, and the like, there are obtained the corresponding : quaternary ammonium salts.

In like manner, using the above procedure, the anion of any of the quaternary ammonium salts of the invention can be exchanged by any other desired anion by forming the corresponding quaternary ammonium hydroxide and reacting the latter with the appropriate acid.

Claims

P. A. 23284 » File I3IO8 Date 21.10.68. WHAT 13 CLAIMED IS 1. A compound of the general formula Wherein R represents lower-alkyl; R^ is selected from the class · consisting of hydrogen, lower-alkyl, and halogen; and is selected from the class consisting of hydrogen, hydroxy, halogen, lower-alky1 , lower-a lkox , lower-alkoxy substituted by a group selected from the class consisting of (a) dihydroxyalkyl from 2 to 5 carbon atoms, inclusive, (b) 2-amino- 1-hydroxyethyl , (c) 5- (2-thio>o xazolidinyl)- , (d) 5- (2-oxooxazolidinyl) and (e) epoxyethyl, the radical -O-C^H^-N"^ wherein C H_ is alkylene from 2 to Ώ6 carbon¾atoms ^n inclusive, and ^ taken individually represent P.A. 232S¾ File 13108 Date. 21.10.68 lower-a llcyl , and and R^ taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and .the radical -0- CmH2m-R5_ wherein CmH2_m is alkylene from 1 to 12 carbon, atoms, inclusive, and is selected from the class consisting of carboxy and lower-carba Ikoxy (b) the addition salts with pharmacologically acceptable acids of those compounds of the above formula which contain an amino substituent; and (c) the quaternary ammonium salts of those compounds of the above formula which contain a tertiary amino sjubstituent , wherein the anion of the quaternary salt is that of a pharmacologically acceptable acid. - 50 - 2 -i- A compound selected from the class consisting of compounds having the formula wherein R represents lower-alk 1; Ri is selected from the Class consisting of hydrogen, lower-alkyl, and ;halogen; and Ra is selected from the class consisting of hydrogen, hydroxy, halogen, lower-alkyl, lower^alkoxy, lower-alkoxy , substituted by a group selected from the class consisting of (a) dihydroxyalkyl from 2 to 5 carbon atoms, inclusive, (b) 2-amino-l-hydroxyethyl, gether with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and the radical -0-CmH2m-Rs wherein CmH2m is alkylene from 1 to 12 carbon atoms, inclusive, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy; (b) the addition salts with pharmacologically acceptable acids of those compounds of the above formula which contain an ami ^ .su,b ti ent j and , (c) the quaternary ammonium salts of those compounds of the above formula which contain a tertiary amino substituent, / P.A.23284^ File 1J.108 22.11.66 wherein the anion of the quaternary salt is that of a pharmacologically acceptable acid. 3· If 2-diphenyl-6-inethoxy~l,2,3»4- etrahydronaphthalene . 4. l-(p-hydroxyphenyl)-2-ph3nyl-6-methoxy-1, 2, 3,4-tetra-hydronaphtiialene. 5. l~j^-(2,3-Iihydroxypropoxy)phenylJ-2-phenyl-6-methoxy-1,2, 3§4- etrahydronaphthalene« 6. A compound selected from the class consisting of 1-jjp-( 2-pyrrolidinoethoxy)phenyl^ -2-phenyl-6-methoxy-1,2,3,4- etrahydronaphthalene and the addition salts thereof with pharmacologically acceptable acids. 7· l-Qp-(2-pyrrolidinoethoxy)phenyl^-2-phenyl-6-methoxy-1, 2, 314-tetrahydronaphthaLene hydrochloride . 8. l-^p-( 2-pyrrolidinoethoxy)phen ^ -S^p s yl-G-methoxy-1,2, 3,4- etrahydronaphthalene « 9. A compound selected from the class consisting of (a) compounds having the formula wherein R represents lower-alliyl; ^ is selected from the class consisting of hydrogen, lower-alkyl.and halogen; and is selected from the class consisting of hydrogen, hydroxy, halogen, 1992 lower-alky1, lower-alkoxy, lower-alkoxy substituted by a group selected from the class consisting of (a) dihydroxyalkyl from of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and the radical -0-CmH2m-R5 wherein CmH2m is alkylene from 1 to 12 carbon atoms, inclusive, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy; (b) the addition salts with pharmacologically acceptable acids of those compounds of ttie above formula which contain an amino substituent and (c) the quaternary ammonium salts of those compounds of the above formula which contain a tertiary amino substituent, wherein the anion of the quaternary salt is that of a pharma-cologically acceptable acid. 1, 2-diphenyl-6-methoxy-l, 2, 3, , 5> 8-hexahydronaphthalene . 1- (p-hydroxyphenyl)-2-phenyl-6-methoxy-l,2, 3 > 5, 8-hexa-hydronaphthalene . A compound selected from the class consisting of l-[p-(2-pyrrolidinoethoxy)phenyl ]-2-phenyl-6-methoxy-l, 2, 3> , 5, 8-hexa-hydronaphthalene and the addition salts thereof with pharma-cologically acceptable acids. 1992 / 1- [p-(2-pyrrolidinoethoxy)phenyl j-2-phenyl-6-methoxy 1,2,3*4, 5, 8-hexahydronaphthalene . A compound selected from the class consisting of (a) compound wherein Ri is selected from the class consisting of hydrogen, lower-alkyl, and halogen; and R2 is selected from the class consisting of hydrogen, hydroxy, halogen, lower-alkyl, lower-alkoxy, lower-alkoxy substituted by a group selected from the class consisting of (a) dihydroxyalkyl from 2 to 5 carbon atoms, inclusive, (b) 2-amino-l-hydroxyethyl, (c) 5-(2- hio^o0 azoli-dinyl)-, (e) epoxyethyl, the alkylene from 2 to 6 carbon atoms, inclusive, R3 and R4 taken individually represent lower-alkyl, and R3 and R4 taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and the radical -0-CmH2m-R5 wherein CmH2m is alkylene from 1 to 12 carbon atoms, inclusive, and R5 is selected from the class consisting of carbox and lower-carbalkoxy; (b) the addition salts with pharmacologically acceptable acids of those compounds of the above formula which contain an amino substituent; and 1992 7 (c) the quaternary ammonium salts of those compounds of 8 the above formula which contain a tertiary amino substltuent, 9 wherein the anion of the quaternary salt is that of a pharma-0 cologically acceptable acid. 1 5, 6-diphenyl-3, * 6, 7> 8-hexahydro-2(lH) -naphthalenone . - - 1 5-(p-hydroxyphenyl) -6-phenyl-;5, , 5, 6, 7, 8-hexahydro-2(lH)- 2 naphthalenone . -1^= -its'. A compound selected from the class consisting of 5-[p- {2- 2 pyrrolldinoethoxy)phenyl ]-6-phen l-3, . 5, 6, 7, 8-hexahydro-2(lH)- 3 naphthalenone and the addition salts thereof with pharmaco- 4 logically acceptable acids, -1*- M- 1 5- [p- (2-pyrrolidinoethoxy)phenyl ]-6-phenyl-3, , 5* 6, 7, 8- 2 hexahydro-2(lH) -naphthalenone. -ii- 1 A compound selected from the class consisting of 2 (a) compounds having the formula 8 9 wherein Ri is selected from the class consisting of hydrogen, 0 lower-alkyl, and halogen j and R2 is selected from the class 1 consisting of hydrogen, hydroxy, halogen, lower-alkyl, lower-2 alkoxy, lower-alkoxy substituted by a group selected from the 1992 class consisting of (a) dlhydroxyalkyl from 2 to 5 carbon atoms n inclusive, (b) 2-amino-l-hydroxyethyl, (c) 5- (2-thio^ooxazoli-dinyl)-, (d) 5- (2-oxooxazolidinyl)-, and (e) epoxyethyl, the radical wherein CnH2n is alkylene from 2 to 6 carbon atoms, inclusive, R3 and R4 taken individually represent lower-alkyl, and R3 and R4 taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and the radical -0-CmH2m-R5 wherein CmH2m is alkylene from 1 to 12 carbon atoms inclusive, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy; (b) the addition salts with pharmacologically acceptable acids of those compounds of the above formula which contain an amino substituent; and (c) the quaternary ammonium salts of those compounds of the above formula which contain a tertiary amino substituent, wherein the anion of the quaternary salt is that of a pharmaco-logically acceptable acid. The process which comprises subjecting a compound having the formula wherein R represents lower-alkyl, Ri is selected from the group consisting of hydrogen, lower-alkyl, and halogen, and X is selected from the group consisting of hydrogen, lower-alkyl, 1992 f halogen, and hydroxy, to reduction using an ethenoid bond reducing agent to obtain the corresponding l, 2, 3j 4-tetrahydro-naphthalene wherein R, Ri, and X have the significance above defined. The process which comprises subjecting a compound having the formula wherein R represents lower-alkyl, x is selected from the group consisting of hydrogen, lower-alkyl, and halogen, and X is selected from the group consisting of hydrogen, lower-alkyl, halogen, and hydroxy, to reduction using lithium and liquid ammonia to obtain a compound having the formula wherein X, R and Ri have the significance hereinbefore defined 1992 The process which comprises subjecting a compound having the formula wherein R represents lower-alkyl, Rx is selected from the group consisting of hydrogen, lower-alkyl, and halogen, and R2 is selected from the class consisting of hydrogen, hydroxy, halogen, lower-alkyl, lower-alkoxy, lower-alkoxy substituted by a group selected from the class consisting of (a) dihydroxyalkyl from 2 to 5 carbon atoms, n inclusive, (b) 2-amino-l-hydroxyethyl, (c) 5-(2-thio^iooxazoli- n rogen a om represen e res ue o a sa ura e e erocyc c radical of from 5 to 7 ring atoms,.. inclusive, and the radical -0-CmH2m-Rs wherein CmHam is alkylene from 1 to 12 carbon atoms, inclusive, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy, to dealkylation using acid hydrolysis to obtain the corresponding compound having the formula 1992 I wherein Ri and R2 are as above defined. The process which comprises subjecting a compound having the formula wherein Ri is selected from the group consisting of hydrogen, lower-alkyl, and halogen, and R2 is selected from the class consisting of hydrogen, hydroxy, halogen, lower-alkyl, lower-alkoxy, lower-alkoxy substituted by a group selected from the class consisting of (a) dlhydroxyalkyl from 2 to 5 carbon atoms, n inclusive, (b) 2-amino-l-hydroxyethyl, (c) 5-(2-thio;^ooxazoli-dlnyl)-, (d) 5-(2-oxob'xazolidinyl)-, and (e) epoxyethyl, the radical is alkylene from 2 to 6 carbon atoms, inclusive, R3 and R* taken individually represent lower-alkyl, and R3 and R4 taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and the radical -0-CmH2m-R5 wherein CmH2m is alkylene from 1 to 12 carbon atoms, inclusive, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy, to treatment with a reagent selected from the class consisting of strong acids and strong bases to obtain a compound having the formula 1992 wherein Ri and R2 are as defined above . The process of claim X$ wherein, when X represents hydroxy in the end product, the latter is alkylated by reaction with an alkylating agent selected from the* class consisting of lower- Ra alkyl halides, ""^N-CnH2n-Hal, wherein CnH2n is alkylene from 2 to 6 carbon atoms, inclusive, Hal is halogen, R3 and R4 taken individually represent lower-alkyl and R3 and R taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and R5-CmH2m-Hal wherein CmH2m is alkylene from 1 to 12 carbon atoms, inclusive, Hal is halogen, and R5 is selected from the class consisting of carboxy and lower-carb-"alkoxy, . and a lower-alkyl halide wherein the alkyl group is substituted by a radical selected from the class consisting of epoxyethyl and dihydroxyalkyl from 2 to 5 carbon atoms, inclusive. ~ 2$- The process of claim Jtf wherein, when X represents hydroxy in the end product, the latter is alkylated by reaction with an alkylating agent selected from the class consisting of lower-alkyl halides, wherein CnH2n is alkylene from 2 to 6 carbon atoms, inclusive, Hal is halogen, R3 and R taken individually represent lower-alkyl and R3 and R4 taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and R5-CmH2m-Hal wherein CmH2m is alkylene from 1 to 12 carbon atoms, inclusive, Hal is halogen, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy, and a lower-alkyl halide wherein the alkyl group 1992 f is substituted by a radical selected from the class consisting of epoxyethyl and dihydroxyalkyl from 2 to 5 carbon atoms, inclusive. The process of claim 2$ wherein, when R2 represents hydroxy in the end product, the latter is alkylated by reaction with an alkylating agent selected from the class consisting of lower-alkyl halides, >N-CnH2ri-Hal, wherein CnH2n s alkylene from 2 to 6 carbon atoms, inclusive, Hal is halogen, R3 and 4 taken individually represent lower-alkyl and R3 and R taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and R5-CmHsm-Hal wherein CraH2m is alkylene from 1 to 12 carbon atoms, inclusive, Hal is halogen, and R5 is selected from the class consisting of carboxy and lower-carbalkoxy, and a lower-alkyl halide wherein the alkyl group is substituted by a radical selected from the class consisting of epoxyethyl and dihydroxyalkyl from 2 to 5 carbon atoms, inclusive. The process of claim 2 wherein, when R2 represents hydroxy in the end product, the latter is alkylated by reaction with an alkylating agent selected from the class consisting of lower-alkyl halides, wherein CnH2n is alkylene from 2 to 6 carbon atoms, inclusive, Hal is halogen, R3 and R taken individually represent lower-alkyl and R3 and R4 taken together with the attached nitrogen atom represent ■ the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and R5-CmH2m-Hal wherein CmH2m is alkylene from 1 to 12. carbon atoms, inclusive, Hal is halogen, and R5 is 1992 selected from the class consisting of carboxy and lower-carbalkoxy, and a lower-alkyl halide wherein the alkyl group is substituted by a radical selected from the class consisting of epoxyethyl and dihydroxyalkyl from 2 to ,5 carbon atoms, inclusive. -28T- -ffl- A process for the preparation of a compound having the formula wherein Ri is selected from the group consisting of hydrogen, lower-alkyl, halogen, and X is selected from the group consisting of hydrogen, lower-alkyl, halogen, and hydroxy,- which comprises subjecting a compound having the formula wherein R represents lower-alkyl and Ri and X are as above defined, to reduction using an ethenoid bond reducing agent to obtain the corresponding 1, 2 , 3, 4-tetrahydronaphthalene, subjecting the latter to reduction using lithium and liquid ammonia to obtain the corresponding 1, 2 , 3, 4, 5, 8-hexahydro-naphthalene having the formula 62 1992 wherein R, Ri and X have the significance above defined, subjecting the latter to dealkylation using acid hydrolysis, and subjecting the 3,4, 5,6,7, 8-hexahydro-2(lH)-naphthalenone so obtained to rearrangement to obtain the desired 4,4a, 5*6,7*8-hexahydro-2(3H)-naphthalenone of the formula set forth above. A process, for the preparation of a compound having the formula wherein R represents lower-alkyl, Ri is selected from the group consisting of hydrogen, lower-alkyl, and halogen, and X is selected from the group consisting of hydrogen, lower-alkyl, halogen, and hydroxy which comprises subjecting a compound having the formula wherein R, Ri, and X are as above defined, to reduction using an ethenoid bond reducing agent to obtain the corresponding 1,2, 3)4-tetrahyd ©naphthalene and subjecting the latter compound to reduction using lithium and liquid ammonia. 30. The process of Claim 2 wherein,when X represents hydroxy in the end product, the latter is alkylated by reaction with an alkylating agent selected from the class consisting of lower-alkyl halides, wherein CnH2n is alkylene from 2 to 6 carbon atoms, inclusive., Hal is halogen, R-j and R^ taken individually represent lower-alkyl and and R^ taken together with the attached nitrogen atom represent the residue of a saturated heterocyclic radical of from 5 to 7 ring atoms, inclusive, and Rc-C H -Hal wherein C H- is alkylene from 1 to 12 5 m 2m m carbon atoms, inclusive, Hal is halogen, and is selected from the class consisting of carboxy and lower-carbalkoxy, and a lower-alkyl halide wherein the alkyl group is substituted by a radical selected from the class consisting of epoxyethyl and dihydrox alkyl from 2 to 5 carbon atoms, inclusive . 31. Compounds of the general formula defined in Claim 1, whenever obtained by a process as claimed in any of Claims 20 to 30. 32. l,2,3,4-Tetrahydronaphthalene8 as defined in Claim 2, substantially as hereinbefore described and with reference to any of the Example