IE47508B1 - Tetralone intermediates - Google Patents

Description

This invention relates to intermediates useful for the preparation of 1,9-dihydroxyoctahydrophenanthrenes and l-hydroxyoctahydrophenthren-9-ones and derivatives thereof having analgesic properties useful for adminis5 tration to mammals including humans. Said 1,9-dihydroxyoctahydrophenanthrenes and 1-hydroxyoctahydrophenanthren9-ones are described and claimed in Patent Specification No. 47505 and are of the formulae:- III wherein Rx is hydrogen, benzyl, benzoyl, alkanoyl of to 5 carbon atoms or -CO-(CH-) NR'R wherein p is 0 or z p an integer from 1 to 4; each of R' and R when taken individually is hydrogen or alkyl of 1 to 4 carbon atoms; R' and R when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrollo, pyrollidino, morpholino and N-alkylpiperazino having from 1 to 4 carbon atoms in the alkyl group; R2 is selected from hydrogen, alkanoyl of 1 to 6 carbon atoms and-benzoyl; Rj is selected from hydrogen, methyl and ethyl; R4 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and benzyl; Z is selected from: (a) alkylene having from one to nine carbon atoms; (b) - (alk2)m-X-(alk2) - wherein each of (alk2) and (alk2) is alkylene having from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk^) plus (alk2) is not greater than 9; m and n are each 0 or 1; X is selected from 0, S, SO and S02; and W is selected from hydrogen, methyl, pyridyl, piperidyl, phenyl, monochlorophenyl, monofluorophenyl and -CH CH-W^, wherein is - 4 selected from hydrogen, phenyl, monochlorophenyl and mono fluorophenyl; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 4, with the proviso that the sum of a and b is not greater than 5.

Compounds of formulae X and II are effective as analgesic agents and are non-narcotic and free of addiction liability. These compounds also have utility as antihypertensives immunosuppressants, tranquilizers, diuretics and as anti-anxiety drugs and as agents for the treatment of glaucoma. Compounds of formula II are useful as intermediates for the formation of analgesic agents of formula I. Compounds of formula III are useful as intermediates for the formation of compounds of the formulae I and II.

According to the present invention, there are provided novel intermediates useful for the preparation of the compounds of formulae I, II and III: such useful intermediates are those of the formula:- wherein R^' is hydrogen, alkanoyl of 1 to 5 carbon 20 atoms, benzyl or benzoyl· and R^, R^·, Z and W are as defined above for the compounds of formulae I, II’and III. 47S08 - 5 The 3,3-{RjR4)-6-(Z-W)-8-(OR1p-1-tetralone of formula IV may be synthesized from an appropriate 5-(Z-W)-3-(CY^)benzyl halide, where Y^ is alkyl of 1 to 4 carbon atoms, preferably methyl, benzyl or substituted benzyl. The reaction sequence is shown in reaction scheme 2. The (OYp-substituent serves as a protected hydroxyl group, the protecting alkyl or aryl group being removed later in the synthesis. When Z is alkylene, Y^ is desirably methyl or benzyl. When Z is (alkpm~X- (alk2)n, Y^ is preferably benzyl or substituted benzyl, since it can be subsequently removed to form a hydroxyl group without detriment to the Z group. A Grignard reagent is first prepared by reacting the substituted benzyl halide with powedered magnesium in a suitable solvent such as tetrahydrofuran. This is then reacted with an appropriate alkylidene malonate derivative, as shown in scheme 2. The alkylidene malonate derivative may be formed by the condensation of a suitable aldehyde of the formula RjCHO or ketone of the formula RjR^CO, with an alkyl cyanoacetate, dialkyl malonate or dicyano malonate.

Preferably, the alkyl group of the malonate ester derivative is of 1 to 3 carbon atoms. The reaction is effected in a suitable solvent such as tetrahydrofuran at a temperature below about 10°C. The product is hydrolysed by treatment with an alkali metal hydroxide in alcohol solution, preferably sodium or potassium hydroxide in methanol or ethanol, followed by acidification. Cyclization to form the 3,3-(RjR4)-6-(Z-W)-8-hydroxy-l-tetralone is conveniently REACTION SCHEME 2 IV - 7 effected by refluxing with agueous hydrogen bromide in glacial acetic acid, when decarboxylation, cyclization and conversion of alkoxy or aryloxy to hydroxy by removal of the Y^ group is effected in the one step. These reactions may be effected stepwise, if desired. The 3,3-(R3R4>-6(Z-W)-8-hydroxy-l-tetralone may be used as a starting material for the synthesis of compounds of formulae I, II and III. Preferably, however, the 8-hydroxy group is protected by reaction with a benzyl halide, methyl iodide or dimethyl sulfate. A preferred protecting group when Z-W is joined to the tetralone ring by oxygen or sulfur is benzyl.

In an alternative method, the Z-W substituent may be introduced during the reaction sequence, as also shown in reaction scheme 2. This is a particularly useful and preferred method for preparation of compounds having an oxygen or sulfur atom linking the Z group to the tetralone ring. Suitable starting materials are 3,5-(OY^)-benzyl halides and the corresponding 3,5-(SY^)-benzyl halides.

Y1 is as previously defined and is preferably methyl or benzyl. The substituted benzyl halide is converted to a Grignard reagent, reacted with an appropriate alkylidene malonate derivative and cyclized, as described previously. The Z-W group is then introduced by reaction with one equivalent of an appropriate Z-W methane sulfonate, which reacts with the 6-hydroxy or 6-thiol group of the tetralone. - 8 The reaction is conveniently effected in the presence of a base, preferably an alkali metal hydride such as sodium or potassium hydride, or an alkali metal carbonate such as potassium or sodium carbonate, in a suitable organic solventsuch as dimethyl formamide or acetone. The reaction is preferably conducted in an inert atmosphere at temperatures between about 60°C and 100°C. The Z-W methane sulfonate is a preferred reagent for introduction of the Z-W group in the 6-position of the tetralone. However, any reagent that will react with the -OH or -SH group and allow introduction of the Z-W group at the 6-position of the cyclized intermediate may be used. Suitable alternative reagents include the corresponding Z-rW halides, preferably the bromide or iodide.

Compounds where the Z group contains -SO- or S02 groups are conveniently prepared by oxidation of compounds containing sulfur in the appropriate position of the 6-(Z-W)-substituent of the tetralone, which are prepared by the methods described above. The oxidation may be effected at any subsequent stage of the synthesis but most conveniently compounds of formula XX are oxidized. Compounds of formula III may also be oxidized to convert S to S02 in the Z group. The oxidation to SO may be carried out by using one equivalent of a peracid such as m-chloroper25 benzoic acid, perbenzoic acid and other such acids, which may be prepared in situ from a mixture of the corresponding carboxylic acid and hydrogen peroxide. The reaction is - 9 conducted at a temperature between about 0°C and 25°C, preferably about 0°C and 10°C. Using two equivalents of a peracid the corresponding compound where Z contains an S02 group are obtained.

-(Z-W)-3-(OY^)-substituted benzyl halides useful for the preparation of the tetralone starting materials are known in the art or may be synthesized by the following procedures. 3-methoxy isophthalaldehydic acid methyl ester is prepared from 3-methoxy isophthalic acid dimethyl ester by reduction with diisobutyl aluminum hydride. The formyl group may then be reacted with Wittig reagents to introduce the Z-W group. By choice of appropriate reagents straight or branched alkylene groups can be introduced. The Wittig reaction is effected by use of an alkylidene triphenylphosphorane. The Z-W substituent is formed by catalytic reduction of the unsaturated side chain.using platinum or palladium on carbon as a catalyst. Reduction of the ester function with excess lithium aluminium hydride in ether at reflux temperature and acidification yields the corresponding 1-(Z-W)-3-methoxy-benzyl alcohol.

The latter is converted to the corresponding benzyl halide by reaction with a thionyl halide, preferably thionyl chloride, at reflux temperature. The formed substituted benzyl halide may be purified if desired by recrystallization, column chromatography or vacuum distillation. For compounds with an -branch in the Z-W side chain, the 3-methoxy - 10 isophthalaldehydic acid dimethyl ester is hydrolyzed by dilute acid or base to yield the half ester acid. The carboxyl group is reacted with thionyl chloride to form the acid chloride, which is then reacted with diethyl malonate as the ethoxy magnesium salt. Hydrolysis by dilute acid and decarboxylation produces methyl 3-methoxy5-acetyl benzoate. The carbonyl group of the acetyl substituent is then converted to the Z-W group by the Wittig reaction and the carbomethoxy group subsequently reduced to form the benzyl halide by the sequences described above.

Substituted benzyl halides of the type where Q' is hydrogen or methyl and Q is alkyl, alkyloxyalkyl and alkylthioalkyl may be prepared by Friedel-Crafts alkylation of m-cresol. Meta substitution is effected under forcing conditions using excess aluminum chloride catalyst and reflux temperatures, see Anhydrous Aluminum Chloride in Organic Chemistry”, Reinhold 20 Publishing Corporation, New York, 1941, page 181. The phenolic group is conveniently protected at this time in anticipation of the formation of a Grignard reagent later - 11 in the synthesis. This can be done by reaction with, for example, methyl iodide, dimethyl sulfate or benzyl chloride. Subsequent bromination using N-bromosuccinimide yields the desired substituted benzyl bromide.

A further method of preparing the substituted benzyl halides useful for preparation of the tetralone intermediates is from l-acetyl-3-nitro-5-carboalkoxy-benzene, where alkoxy is of 1 to 4 carbon atoms. See Chem. Abs. 1366a, Zh. Obatsch Khim 32, 293 (1962). The carbonyl group of the acetyl substituent is reacted with Wittig reagents to introduce the Z-W side chain as previously described, followed by catalytic reduction over platinum or palladium on carbon. The reduction is effective to reduce both the double bond in the Z group and to convert the nitro group to amino. Diazotisation of the amino group with hydrochloric acid and sodium nitrite in water yields the corresponding phenol which is then protected by reaction with methyl iodide, dimethyl sulfate or benzyl chloride. The ester function is then reduced with lithium aluminum hydride to yield the benzyl alcohol. The corresponding benzyl halide is prepared by reaction of the benzyl alcohol with thionyl chloride or phosphorous pentachloride. 3-Methoxy isophthalaldehydic acid methyl ester, 3methoxy-5-acetyl benzoate and analagous compounds may also be used in an alternative synthesis of the substituted - 12 tetralorie intermediates of formula IV, which is especially useful when W is a nitrogen-containing heterocyclic group. It is also a preferred method for preparing compounds where Z is -(alk^J^-S-CalkjJjj- and m is one.

In this method, the carbonyl function of the formyl or acetyl substituent is first protected by forming an acetal or ketal. This may be effected by reaction with a suitable glycol such as, but not limited to, ethylene glycol in the presence of a catalytic amount of a strong acid such as p-toluenesulfonic acid or sulfuric acid. The protected compound is then converted to a substituted benzyl halide, via reduction to the substituted benzyl alcohol and subsequent reaction with a thionyl halide.

The protected benzyl halide so formed is converted to a Grignard reagent, reacted with an appropriate alkylidene malonate derivative, followed by hydrolysis and cyclization, as described in detail for these reaction steps previously, to form a 3,3-(RjR4)-8-hydroxy-l-tetralone having at the 6-position the acetal- or ketal-protected formyl or acetyl group, depending on the starting material. The carbonyl function of the 6-substituent is regenerated by hydrolysis of the acetal or ketal to remove the protecting group.

The Z-W substituent is then introduced by the reaction of the carbonyl group with a Wittig reagent as previously described. The carbonyl group at the 1-position of the tetralone ring reacts relatively slowly with Wittig reagents, thus allowing preferential reaction at the 647508 - 13 substituent. However, if desired, increased yields of the (Z-W)-substituted tetralone can be obtained by first protecting the carbonyl group at the 1-position, for example by formation of a ketal.

The invention is illustrated by the following Examples: EXAMPLE 1 3,5-Dimethoxybenzylchloride Over a period of 20 minutes a solution of 150 g (1.26 moles) of thionyl chloride in 0.65 1 of ether was added to 100 g (0.59 moles) of 3,5-dimethoxybenzyl alcohol and 6.6 ml of pyridine in 1.35 1 of ether. After stirring for 3 hours the solution containing the product was separated from the residual dark oil, concentrated, and the crude product was redissolved in 1 1 of ether, washer with water (3 x 250 ml), dried (brine, magnesium sulfate), filtered, and reconcentrated to give a dark oil which was vacuum distilled: b.p. 115°C - U8°C at 0.4 mm Hg. Upon standing, fractions containing the desired compound solidified to give 95.3 g (86%) of white solid, m.p. 43°C-45°C.

EXAMPLE 2 2-Cyano-3,3-dimethyl-3-(31,5'-dimethoxyphenyl)butyric acid A tetrahydrofuran solution of 3,5-dimethoxybenzyl magnesium chloride (prepared from 2.05 g (84 mmoles) of - 14 powdered magnesium and 15.0 g (80.4 mmoles) of 3,5dimethoxybenzyl chloride in 300 ml of dry tetrahydrofuran was added dropwise to a solution of 9.23 g (60.3 mmoles) of ethyl isopropylidene cyanoacetate and 0.40 g of cuprous chloride in 25 ml of tetrahydrofuran while maintaining the reaction temperature below 10°C. After the addition was complete, the reaction mixture was warmed to room temperature, stirred overnight and then poured into 300 ml cold saturated aqueous ammonium chloride.

The solution was extracted 3 times with 400 ml of ether and the combined extracts were washed 2 times with 400 ml of water, dried (brine, magnesium sulfate) and concentrated to give 19.4 g of an oil which was hydrolyzed by treatment with ageuous ethanolic potassium hydroxide at room temperature for 15 minutes. The reaction mixture was concentrated to remove the ethanol and the resulting residue was taken up in a mixture of 300 ml ethyl acetate and 150 ml water. The ethyl acetate layer was separated and washed with 150 ml of water followed by 100 ml of saturated sodium bicarbonate. Acidification of the combined aqueous solutions with 10% hydrochloride acid at 0°C gave an oil which was separated by extracting 4 times with 150 ml of ether. The ether extracts were combined washed with 150 ml of water, dried (brine, magnesium sulfate), filtered, and concentrated to yield 11.1 g (50%) of the desired compound as an oil. - 15 NMR: CDClg! & : 1.1 (S,3H), 1.2(S,3H), 2.7(S,2H), 3.4(S,1H), 3.7(S,6H), 6.3(S,3H), 10.0(lH).

EXAMPLE 3 3,3-Dimethyl-6,8-dihydroxy-l-tetralone 5 The 2-cyano-3,3-dimethy1-3-(3'-5'-dimethoxyphenyl) butyric acid (11.1 g; 40.1 mmoles) was treated with 170 ml of 48% agueous hydrogen bromide and 170 ml of glacial acetic acid at reflux overnight. After cooling to room temperature and concentrating, the reaction mixture was treated with 300 ml of water and extracted with ethyl acetate (3 x 150 ml). The combined extracts were dried (brine, magnesium sulfate) and concentrated to give a dark foam (7.92 g), which was dissolved in a minimum amount of benzene/ethyl acetate and chromatographed on 350 g of silica gel eluted with benzene followed by 20% ethyl acetate/benzene. The fractions containing the desired compound were combined and concentrated to an oil, which crystallized after treatment with hexane, 4.04 g (49%); m.p. 115° - 116°C. Recrystallization from ethyl acetate/hexane gave the desired product as light tan needles; m.p. 116°-117°C. ^12^14^3^! Calc.: C: 69.89%; H: 6.84%; Fd. C: 70.26%, H: 6.74%. - 16 EXAMPLE 4 3,3-Dimethyl-6-(5'-phenyl-21-pentyloxy)-8-hydroxy-ltetralone A 1.68 g (8.15 mmoles) portion of 3,3-dimethyl-6,85 dihydroxy-1-tetralone and 2.25 g (16.3 mmoles) of potassium carbonate were suspended in 8 ml of dry dimethyl formamide and reacted with 2.17 g (8.97 mmoles) of 5-phenyl-2-pentyl methanesulfonate under nitrogen at 80°C for 3.5 hours.

After cooling to room temperature the reaction was poured into 100 ml of ice water and extracted with ethyl acetate (2 x 75)ml), acidified with 10% hydrochloric acid and further extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with water (4 x 40 ml), dried (brine, magnesium sulfate), filtered, and concen15 trated to a dark oil which was chromatographed on 120 g j; of silica gel eluted with benzene/hexane (1:1) followed |. by benzene. Combination and concentration of the proper fractions afforded 2.72 g (96%) of the desired compound as an oil.

NMR: CDClj: 1.0(S,6H gemdimethyl), 1.3(D,3H, J=7Hz, side chain CH3) 1.7(M,4H,ethylene), 2.5(S,2H, (X -methylene), 2.7 (S,2H,benzyl methylene), 2.7(M,2H, benzyl methlene), 4.1-4.6 (Μ,IH,methine), 6.1(M,2H, aromatic), 7.1-7.2(M,5H, aromatic), 13.0(S,1H,phenol). 47S08 - 17 EXAMPLE 5 3,3-Dimethyl-6-(5'-phenyl-21-pentyloxy)-8-benzyloxy-ltetralone A solution of 1.36 g of 3,3-dimethyl-6-(5'-phenyl2’-pentyloxy)-8-hydroxy-l-tetralone in 7 ml of dry dimethyl formamide was slowly added to 206 mg of pentane washed 50% sodium hydride. After stirring for 1 hour at room temperature, the dark brown mixture was chilled to 2° in an ice bath, treated dropwise with 0.475 ml of benzyl bromide, stirred for 0.5 hours at 0°C then warmed to room temperature and stirred for an additional 3 hours before being poured into a mixture of ice cold IN hydrochloric acid and ether. The ether layer was separated and the aqueous was extracted once more with ether. The combined organic layers were washed with water, dried (brine, magnesium sulfate) and concentrated to a yellow oil which was chromatographed on 100 g of silica gel eluted with ether/hexane (1:1). Combination and concentration of the appropriate fractions gave 1.26 g (74%) of the desired compound.

NMR: CDClj: £ : 7.7-6.9(M,10H,phenyl aromatics), 6.3 and 6.2 (two one-proton doublets, J=2Hz, aromatic), 5.1(S,2H, benzyloxy methylene), 4.7-4.2(M,1H,methine), 2.8(S,2H,benzylic methylene) 2,7 (T,2H,benzylic methylene) 2.5 (S,2H, benzylic methylene) 2.7 (T,2H, benzylic methylene) 2.5(S,2H, C*--methylene) 1.9-1.5 (M,4H,ethylene) 1.3 (D, J=7Hz, 2H, methyl) 1.0(S,6H, gem-dimethyl). - 18 EXAMPLE 6 6.8- Dimethoxy-1-tetralone The tetralone was prepared according to the procedure of Huisgen, Seidl, and Wimmer; Ann., 677, 21 (1964), m.p. 58O-61°C, (lit. m.p. - 62°-64°C).

EXAMPLE 7 6.8- Dihydroxy-1-tetralone The 6,8-dimethoxy-1-tetralone (3.0 g; 14.0 mmoles) was refluxed overnight with 20 ml of 48% agueous hydrogen bromide and 20 ml of glacial acetic acid. After cooling to room temperature, the reaction mixture was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried (brine, magnesium sulfate) and concentrated to afford a red solid which upon trituration with ether gave the desired compound as an off-white solid, 1.77 g (71%); m.p. 209°-210°C.

NMR: CDC13: g : 2.0(Μ,2H,methylene), 2.6 (M,4H, methylene); 6.2 (S,2H aromatic), 9.2 (broad singlet, IH, 20 hydroxyl) and 12.65 (S,1H, hydroxyl).

EXAMPLE 8 6-(51-phenyl-21-pentyloxy)-8-hydroxy-l-tetralone A 1.77 g (9.9 mmoles) portion of 6,8-dihydroxy-ltetralone and 2.7 g (19.8 mmoles) of potassium carbonate - 19 were suspended in 20 ml of dry dimethyl formamide and reacted with 2.6 g (10.8 mmoles) of 5-phenyl-2-pentyl methanesulfonate under nitrogen, at 80®C for 3.5 hours. After cooling to room temeprature the reaction was poured into 100 ml of ice water and extracted with ethyl acetate (2 x 75 ml), acidified with 10% hydrochloric acid and further extracted with ethyl acetate (2 x 50 ml).

The combined organic phases were washed with water (4 x 40 ml), dried (brine, magnesium sulfate), filtered and concentrated to a dark oil which was chromatographed on 130 g of silica gel eluted with hexane/ether (1:1) Combination and concentration of the proper fractions afforded 2.3 g; (72%) of the desired compound as an oil.

NMR: CDClj! $ : 1.4 (d,3H, side chain methyl), 1.8 and 2.2 (broad asborb. m, 12H, methylene), 4.4 (broad singlet, IH, methine) 6.2(S,2H aromatic); 7.2 (S,5H, aromatic), 12.65(S,1H, hydroxyl).

EXAMPLE 9 6-(5*-pheny1-2'-pentyloxy)-8-benzyloxy-l-tetralone A solution of 2.3 g of 6-(5'-pheny1-21-pentyloxy)8-hydroxy-l-tetralone in 15 ml of dry dimethyl formamide was slowly added to 187 mg of 50% soidum hdyride washed with pentane. After stirring for 1 hour at room tempera25 ture, the mixture was chilled to 2° in an ice bath, n. 47508 - 20 treated dropwise with 0.92 ml of benzyl bromide, stirred for 0.5 hours at 0°C then warmed to room temperature and stirred overnight before being poured into a mixture of ice cold IN hydrochloric acid and ether. The ether layer was separated and the aqueous layer was extracted once more with ether. The combined organic layers were washed with water, dried (brine, magnesium sulfate), and concentrated to an oil which was chromatographed on 120 g of silica gel eluted with hexane/ethyl acetate 1° (3:1). Combination and concentration of the appropriate fractions gave 2.21 g (77%) of the desired compound.

NMR: CDClj:£ : 1.25 (D,3H, side chain methyl), 1.75 and 2.1 (M,6H, methylene) 2.8 (M,6H, methylene), 4.4 (broad singlet, IH, methine), 5.2 (S,2H, benzylic), 6.3 (m, 2H, aromatic), 7.2 (S & Μ, 10H, aromatic).

EXAMPLE 10 3-Methoxyisophthalaldehydic acid methyl ester To a -78® to -100° solution of 1.0 mol of 3-methoxyisophthalic acid dimethyl ester in 1-10 1 of toluene is slowly added 1.0 mol of diisobutylaluminum hydride as a IM solution in n-hexane. The reaction is stirred for 3 hours after the addition and then quenched by the addition of 10 mol of anhydrous methanol. The reaction is allowed to warm to room temperature and stirred until a filterable precipitate forms: The reaction is filtered and the filtrate evaporated to a residue. The residue is purified - 21 by crystallization, distillation or chromatography to yield 3-methoxyisophthalaldehydic -acid methyl ester.

EXAMPLE 11 3-chloromethyl-5-methoxybenzaldehyde ethylene glycol acetal A 0.1 mol portion of 3-methoxyisophthalaldehydic acid methyl ester is heated overnight in 200-300 ml of ethylene glycol containing a catalytic amount of ^.-toluene sulfonic acid. The reaction is cooled, diluted with dilute aqueous sodium bicarbonate and extracted with ether. After dyring with anhydrous sodium sulfate the ether exacts are concentrated to yield a mixture of methyl and yS -hydroxy ethyl esters of the acetal. This mixture is dissolved in ether or tetrahydrofuran and added to an excess (0.1 mol) of lithium aluminum hydride in ether.

After the reduction is complete the mixture is worked-up by addition of water and 6N sodium hdyroxide to precipitate the inorganic salts. The ether is dri ed and evaporated to give the crude benzyl alcohol-acetal. This benzyl alcohol-acetal is heated with 150 ml of thionyl chloride in ether with a catalytic amount of pyridine. After evolution of gases is complete the excess thionyl chloride is removed under vacuum. The benzyl chloride is then purified by column chromatography or vacuum distillation. - 22 EXAMPLE 12 3-butyl-6-formyl-8-hydroxy-l-tetralone The Grignard reagent of 3-chloromethyl-5-methoxybenzaldehyde ethylene glycol acetal is formed and added to ethyl 2-cyano-2-heptenoate (R. Carrie, R. Bougot and B. Potteau, Compt. Rend. 259, 2859 (1964) using procedures described in Example 2. The adduct thus obtained is cyclized to the tetralone, the methoxy ether cleared and the acetal hydrolyzed using the hydrogen bromide procedure described in Example 3.

EXAMPLE 13 3-buty1-6-formy1-8-benzyloxy-1-tetralone The product of Example 12 is treated with sodium hydride and benzyl bromide according to the procedures described in Example 15.

EXAMPLE 14 3-butyl-6-[61-(21-pyridyl) hexyl]-8-hydroxy-l-tetralone A mixture of 0.015 mol of 2-(5*-bromopentyl)pyridine (J. Krapcho and W. A. Lott, O.S. Patent No. 2,918,470) and 0.015 mol of triphenylphosphine in 15 ml of xylene is refluxed for 18 hours, cooled to room temperature, filtered and the resulting triphenylphosphonium bromide is washed with ether and dried. Under a nitrogen atmosphere a mixture of 0.011 mol of this triphenylphosphonium bromide in 15 ml of dimethylsulfoxide and 0.011 mol of 3-butyl-647508 - 23 formyl-8-benzyloxy-l-tetralone in 10 ml of tetrahydrofuran is added dropwise to a slurry of 0.57 g of 50% sodium hydride in 5 ml of tetrahydrofuran while maintaining the temperature at 0.5®'. After the addition is completed the reaction is stirred for another hour at 0.5®, concentrated under vacuum, diluted with about 60 ml of water and acidified with 6N hydrochloric acid. The aqueous solution is extracted with benzene to remove the triphenylphosphine oxide and the agueous layer is made basic and extracted with ethylacetate. Evaporation of the ethylacetate gives the intermediate alkene as an oil. A mixture of this oil, 25 ml of absolute methanol, 0.15 ml of concentrated hydrochloric acid and 0.3 g of 10% palladium on carbon is hydrogenated in a Parr shaker for one day at 55 psi hydrogen. The mixture is filtered through celite and concentrated under vacuum. Addition of ether yields the desired product as the hydrochloride salt, which is filtered off, washed with ether and dried.

The free base is obtained by dissolving the hydrochloride salt in agueous ethanol adding agueous sodium bicarbonate, extracting with ethylacetate, drying and removing the solvent under vacuum.

EXAMPLE 15 Methyl 3-acetyl-5-methoxybenzoate A solution of 0.5 mol of dimethyl 3-methoxy-isophthalate is dissolved in aqueous methanol containing an equivalent - 24 amount (0.5 mol) of potassium hydroxide. The reaction is warmed to about 50°C and stirred until the hydrolysis is complete. Acidification with 6N hydrochloric acid, extraction with ether, and evaporation of the ether yields the half-ester which is added to 300 ml of thionyl chloride and heated until evolution of sulfur dioxide and hydrogen chloride ceases. The excess thionyl chloride is removed under vacuum and the half-ester-acid chloride is purified by vacuum distillation. A 0.2 mol portion of this com10 pound in 75 ml of ether is added over a 15 minute period to 0.22 mols of a solution of ethoxymagnesiummalonic ester (prepared by the method of Reynolds and Hauser, Org. Syn. Col. Vol. IV, 708 (1963)) while heating at reflux. The mixture is cooled, shaken with dilute sulfuric acid to dissolve the solids, the ether phase separated, the aqueous layer extracted with ether and the combined ether layers washed with water and concentrated. The resulting material is added to a solution of 60 ml of glacial acetic acid, 7.6 ml of concentrated sulfuric acid and 40 ml of water and heated under reflux for 4 hours or until no more carbon dioxide is evolved. The reaction mixture is concentrated and taken up in ether, dried and the ether evaporated to give 3-acetyl-5-methoxybenzoic acid. Reaction of this acid with thionyl chloride, followed by addition of methanol to the acid chloride yeilds methyl 3-acetyl-5-methoxy-benzoate which is purified by vacuum distillation. - 25 EXAMPLE 16 3-chloromethyl-5-methoxyacetophenone ethylene glycol ketal Methyl 3-acetyl-5-methoxybenzoate is reacted with ethylene glycol followed by reduction with lithium aluminumhydride and converted to the benzyl chloride using the procedures described in Example 11.

EXAMPLE 17 3-methyl-3-ethyl-6-acetyl-8-hydroxy-l-tetralone The Grignard reagent of 3-chloromethyl-5-methoxyacetophenone ethylene glycol acetal is formed and added to ethyl 2-cyano-3-methyl-2-pentenoate (F. S. Prout et. al., Org. Syn. Col. Vol. IV, 93 (1963) using the procedures described in Example 2. The adduct obtained is cyclized to the tetralone, the methoxy ether cleaved and the ketal hydrolized using the procedure described in Example 3.

EXAMPLE 18 3-methyl-3-ethyl-6-acetyl-8-benzyloxy-l-tetralone The product of Example 17 is treated with sodium hydride and benzyl bromide according to the procedures in Example 5.

EXAMPLE 19 3-methyl-3-ethyl-6-[6*-(N-methyl-2'-piperidyl)-2'-pentyl] -8-hydroxy-l-tetralone N-methyl-2-(3'bromopropyl)-piperidine (W. L. Meyer and N. Sapionchioy, J. Am. Chem. Soc. 86, 3343 (1964) is - 26 converted to the triphenylphosphorone, reacted with the product of Example 18 and catalytically reduced to the desired compound according to the procedures described in Example 14.

EXAMPLE 20 3-ethyl-6-formyl-8-hydroxy-l-tetralone The Grignard reagent of 3-chloromethyl.-5-methoxybenzaldehyde ethylene glycol acetal produced as in Example 21 is formed and added to ethyl 2-cyano-2-pentenoate (f. D. Popp and A. Catals, J. Org. Chem., 26, 2738 (1961) using procedures described in Example 21. The addition product obtained is cyclized to the tetralone, the methoxy ether cleaved and the acetal hydrolyzed using the aqueous hydrogen bromide procedure described in Example 3.

EXAMPLE 21 3- ethyl-6-formyl-8-benzyloxy-l-tetralone The product of Example 20 is treated with sodium hydride and benzyl bromide according to the procedure described in Example 5.

EXAMPLE 22 4- cyclohexylbutyloxy chloromethyl ether 4-cyclohexylbutyric acid (Aldrich) is reduced with excess lithium aluminum hydride in ether to yield 447508 - 27 cyclohexy1-1-butanol (D. S. Hiers and R. Adams, J. Am. Chem. Soc., 48 2385 (1926)) which is chloro-methylated with hdyrogen chloride and formaldehyde to yield the desired compound.

EXAMPLE 23 3-ethyl-6-cyclohexylbutoxyethyl-8-hydroxy-l-tetralone 4-cyclohexylbutoxymethyl chloride is formed by the method of Example 22, converted to the triphenylphosphorone, reacted with the product of Example 21 and is then reduced catalytically to the desired compound using procedures analogous to those described in Example 14.

EXAMPLE 24 Ethyl 2-cyano-3-benzyl-2-penetenoate l-phenyl-2-butanol (0.12 mol) is condensed with ethylcyanoacetate (0.10 mol) using the procedure of Prout et al (Org. Synth. Coll. Vol. IV, 93, (1963)).

EXAMPLE 25 3-ethyl-3-benzyl-6-formy1-8-hydroxy-l-tetralone The Grignard reagent of 3-chloromethyl-5-methoxy20 benzaldehyde ethylene glycol acetal of Example 11 is formed and added to ethyl 2-cyano-3-benzyl-2-pentenoate using the procedures described in Example 2. The adduct obtained is cyclized to the tetralone, the methyl ether cleaved, and the acetal hydrolyzed using the aqueous hydrogen bromide procedure of Example 3. - 28 EXAMPLE 26 3-ethyl-3-benzyl-6-£ormyl-8-benzyloxy-l-tetralone The product of Example 25 is benzylated with benzyl bromide as described in Example 5.

EXAMPLE 27 3-ethyl-3-benzyl-6-carbethoxyethyl-8-hydroxy-1-tetralone Ethyl bromoacetate is converted to the triphenyl phosphorone, reacted with the product of Example 26 and reduced catalytically to the desired compound using procedures analogous to those described in Example 14.

EXAMPLE 28 3-ethyl-4-benzyl-6-(3'hydroxypropyl)-8-hydroxy-l-tetralone ethylene glycol ketal A 0.05 mol portion of the product of Example 27 is 15 added to 50 ml of ethylene glycol containing 0.1 g of p-toluene sulfonic acid. After heating for 2-3 days the reaction is cooled, neutralized with ageuous sodium bicarbonate and extracted with ether. The ether layer is dried and concentrated. The residual ketal is added directly to 0.05 mol of lithium aluminumhydride in ether and refluxed. After the reduction is complete the mixture is worked up by the addition of water and 6N sodium hydroxide to precipitate the inorganic salts.

The ether is dried and evaporated to give the crude alcohol-ketal. - 29 EXAMPLE 29 3-ethyl-3-benzyl-6-(3'-mesyloxypropyl)-8-mesyloxy-1tetralone ethylene glycol ketal 0.03 mol of the product of Example 28 is dissolved in tetrahydrofuran containing 0.12 mol of triethyl amine and cooled to 0-5°. Methane sulfonyl chloride (0.07 mol) is added dropwise, the reaction allowed to come to room temperature and stirred for another hour. The triethylamine hydrochloride is removed by filtration and the tetrahydrofuran concentrated and the residue is dissolved in chloroform, wash with water, dried and concentrated to the desired product which is used without further purification.

EXAMPLE 30 3-ethyl-3-benzyl-6-(3'-ethyl thiopropyl)-8-hydroxy-ltetralone Under a nitrogen atmosphere 0.02 mol of the product of Example 29 was dissolved in 25 ml of dimethyl formamide and 0.04 mol of sodium ethyl mercaptide is added and the mixture stirred at room temperature overnight. The mixture is then heated to 70° for 3 hours, cooled, poured into water, then acidified with aqeuous hydrochloric acid and stirred for several hours. Extraction with ethylacetate, drying the extracts and evaporation of the solvent give the crude product which is purified by chromatography. - 30 EXAMPLE 31 3,3-dimethy1-6-(2'-pyridylmethyloxy)-8-hydroxy-l-tetralone A 1.68 g (8.2 mol) portion of 3,3-dimethy1-6,8dihydroxy-1-tetralone prepared as in Example 3 and 2.25 g (16.3 mol) of potassium carbonate is suspended in ml of dry dimethyl formamide and reacted with 1.25 g (9 mol) of 2-picolyl chloride under nitrogen at 50-80® for 4-5 hours. After cooling the reacting mixture is poured into 100 ml of ice-water acidified with hydrochloric acid, made basic with sodium bicarbonate and extracted with chloroform and ethylacetate. The combined organic phases are washed with water, dried (brine and sodium and sulfate), filtered and concentrated to an oil/is chromatographed to yield the desired product.

EXAMPLE 32 Methyl 3-(1',21-dimethylheptyl)-5-methoxybenzoate A mixture of 0.03 mol of 2-bromoheptane and 0.03 mol of triphenylphosphine in 30 ml of xylene is refluxed for 18-24 hours, cooled to room temperature and the resulting triphenyl phosphonium bromide is filtered, washed with ether and dried. A mixture of this material (0.022 mol) dissolved in 30-50 ml of dimethyl sulfoxide under a nitrogen atmosphere and 0.022 mol of methyl 3-acetyl-5-methoxybenzoate formed as in Example 25 in io ml of tetrahydrofuran is added dropwise to a slurry of 1.2 g of 50% sodium hydride in 10 ml of tetrahydrofuran while maintaining the temperature at 0-5°. After the - 31 addition is completed the reaction is stirred overnight at room temperature, concentrated under vacuum, diluted with 100-150 ml of water and the product extracted with pentane-ether. The extracts are combined, washed with water, dried and the solvents removed under vacuum.

The alkene thus obtained is purified by chromatography on silica gel.

This alkene is dissolved in 50 ml of absolute methanol and 0.3 ml of concentrated hydrochloric acid and hydrogenated for one day at 55 psi of hydrogen on a Parr shaker containing 0.3 g of palladium on carbon.

The reaction mixture is then filtered through celite and concentrated under vacuum and chromatographed or vacuum distilled to obtain the desired product.

EXAMPLE 33 3-(1',2'-dimethylheptyl)-5-methoxybenzyl chloride A 0.01 mol portion of methyl 3-(1'^'-dimethylheptyl) -5-methoxybenzoate is dissolved in tetrahydrofuran and added to 0.01 mole of lithium aluminum hydride in tetrahydrofuran. After the reduction is complete the mixture is worked-up by addition of water and 6N sodium hydroxide to precipitate the inorganic salts. The tetrahydrofuran is dried and evaporated to give the crude benzyl alcohol. This benzyl alcohol is heated with thionyl chloride following the procedures in Example 1.

Claims (1)

1. A compound having the formula: wherein R’^ is hydrogen,alkanoyl of 1 to 5 carbon atoms, benzyl or benzoyl; R 3 is hydrogen, methyl or ethyl; is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl; Z is selected from: (a) alkylene having from one to nine carbon atoms? or (b) -(alkj) m -X-(alkj) n - wherein each of (alk^) and (alkj) is alkylene having from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk^) plus (alkj) is not greater than 9; m and n are each 0 or 1; X is 0, S, SO or SOj? and W is hydrogen, methyl, pyridyl, piperidyl, phenyl, monochlorophenyl, monofluorophenyl or -CH ’Wa' Wb CH-Wj, wherein is - 33 hydrogen) phenyl, monochlorophenyl or monofluorophenyl; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 4, with the proviso that the sum of a and b is not greater than 5.