NO167732B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE, AROMATIC, POLYCYCLIC DERIVATIVES. - Google Patents

Description

The present invention relates to an analogous method for the production of therapeutically active polycyclic, aromatic compounds.

These polycyclic aromatic derivatives are useful for use in the systemic and topical treatment of dermatological diseases associated with keratinization disorders (differentiation - proliferation) and dermatological disorders or others, with inflammatory and/or immuno-allergic components. They are also useful in the treatment of degenerative diseases of the connective tissue and exhibit an antitumoral activity. Besides this, these derivatives can be used in the treatment of atropia, be it cutaneous or respiratory, and in the treatment of rheumatoid psoriasis.

The polycyclic aromatic derivatives produced according to the present invention can be represented by the following general formula (I)

where X represents -CH=CH-, 0 or S,

R! and R2, each independently represents hydrogen, straight-chain or branched alkyl having from 1-6 carbon atoms, alkoxy having from 1-6 carbon atoms, 1-adamantyl, or Rj and R2 together with the adjacent carbon atoms in the naphthalene ring form a 5 - or 6-membered ring optionally substituted with at least one lower alkyl group or interrupted by an oxygen atom,

R3 represents -CH2OH or -COR4 or -CH3 when R± and R2 together form a ring having a 5- or 6-membered carbocyclic ring,

R 4 represents -OR 5 or

R5 represents hydrogen, alkyl of 1-6 carbon atoms,

monohydroxy lower alkyl,

r' and r" represent hydrogen or lower alkyl, or they together form a morpholine ring, with the proviso that R^ and R2 in formula (I) are different from hydrogen when X = S and R3 = -COOCH3, and the salts of said polycyclic aromatic derivatives of formula I.

By lower alkyl is meant a group that has from 1-4 carbon atoms, mainly methyl, ethyl, isopropyl, butyl and tert. butyl.

By monohydroxyalkyl is meant a group containing 3-6 carbon atoms and from 2-5 hydroxy groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or the group pentaerythritol.

Representative alkoxy groups have from 1-6 carbon atoms which include methoxy, isopropoxy and tert.butoxy.

When the group r<1> and r" together form a heterocycle, this is preferably a morpholine group.

When the compounds according to the present invention are in the form of a salt, they can be salts of an alkali metal or an alkaline earth metal or of zinc, or they can be salts of an organic amine when they have at least one free acid function (R3= COOH), or they can be salts of a mineral acid or organic acid, mainly the hydrochloride, hydrobromide or citrate when they have at least one amino function.

Particularly preferred compounds of formula I prepared according to the present invention are those in which R3 = COOR5 and more particularly those corresponding to the formulas:

where R 5 represents hydrogen or alkyl, and R 2 represents a branched lower alkyl group; where R 5 represents hydrogen or alkyl; where R 1 represents tert-butyl or 1-adamantyl, and R 5 represents hydrogen or alkyl; where X represents 0 or S, and R 5 represents hydrogen or alkyl. Representative compounds of formula I include: p-(6-tert.butyl-2-naphthyl)benzoic acid,

p-(5,6,7,8-tetrahydro-5,5,8k8-tetramethyl-2-anthracenyl)ben-

zoic acid and its ethyl, 2-hydroxyethyl and 2,3-dihydroxypropyl esters,

the diethylamide of p-(6-tert.butyl-2-naphthyl)-benzoic acid, the monoethylamide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid,

p-(6-Methoxy-2-naphthyl)-benzoic acid and its methyl ester, p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzyl alcohol,

2-(p-methylphenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene,

The p-hydroxyphenylamide of p-5,6,7,8-tetrahydro-5-5,8,8-tetra-methyl-2-anthracenyl-benzoic acid,

p-(7-(1-adamontyl)-6-methoxy-2-naphthyl)-benzoic acid and its methyl ester,

p-(7-tert.butyl-6-methoxy-2-naphthyl)-benzoic acid and its methyl ester,

p-(7-(1-adamantyl)-6-hydroxy-2-naphthyl)-benzoic acid and its methyl ester,

5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid and its methyl ester,

the ethyl amide of 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid,

the morpholide of 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid,

2-hydroxyethyl 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylate,

p-(3,4(2H)-dihydro-4,4-dimethyl-7-naphtho(2,3-b)pyranyl)-benzoic acid and its methyl ester.

Although several different synthesis methods are conceivable for the preparation of the compound of formula I, it is preferred to use the method represented by the following reaction core:

R and R<1> represent an alkyl radical or together form a dioxane or dioxolane ring.

According to this method, a Wittig or Wittig-Horner coupling reaction is carried out between an aromatic aldehyde (1) or a pentavalent phosphorus derivative (2).

In the derivative (2), the group A can represent either a tri-arylphosphonium group with the formula -P(X')+3<Y>~ where X<1> is aryl, and Y is the anion from an organic or inorganic acid or

a dialkoxyphosphinyl group of formula

where Z is alkoxy, preferably -OC2H5.

When A represents ~p(X*)+ 3Y - the coupling reaction is carried out in the presence of an alkali metal alcoholate, such as sodium methylate, or in the presence of an alkylene oxide optionally substituted with an alkyl group, in a solvent such as methylene chloride or dimethylformamide. The reaction temperature varies between 0°C and the boiling temperature of the reaction mixture.

When A represents - (Z)2>

the condensation reaction is carried out in the presence of a base and preferably in the presence of an inert organic solvent, e.g. by means of sodium hydride or lithium dialkylamide in benzene, toluene, dimethylformamide (in case sodium hydride is used), tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or also by means of an alcoholate, e.g. using

sodium methylate in methanol or potassium tert.butylate in THF at temperatures between -80°C and the boiling temperature of the reaction mixture. The condensation can also be carried out using a mineral base such as KOH or NaOH in an organic solvent such as tetrahydrofuran or under "phase transfer" conditions.

A ring ether capable of complexing the metal cation contained in the base can be added to the reaction mixture to improve its strength.

The intermediate product of formula III is mainly obtained in the form of a mixture of trans isomers (E) and cis isomers (Z) which can be separated by chromatography although the mixture of the isomers can also be used as such in the following steps.

The cyclization-aromatization reaction is carried out in a chlorinated solvent such as dichloromethane or chloroform in the presence of a strong acid such as sulfuric acid or p-toluenesulfonic acid or a silyl ester of a strong acid such as e.g. trifluoromethanesulfonates of trimethylsilyl as catalyst.

When the (Z) isomer of the compound of formula III or a mixture of the (E)-(Z) isomers is used, the cyclization-aromatization reaction must be carried out under UV irradiation to isomerize the (Z) isomer to its (E) isomer.

In reality, the isomers (Z) under these reaction conditions do not lead to the expected compounds of formula

IN.

This cyclization-aromatization reaction is preferably carried out at room temperature.

The aromatic aldehydes of formula (1) are either commercially available or easily available by means of known synthesis methods.

The preparation of the pentavalent phosphorus derivative with formula (2) can be carried out according to the following reaction core:

According to this method, a coupling reaction is achieved between an alkylhalogen ester (4) and an acrolein dialkyl acetal (5) in the presence of a palladium salt and a base such as triethylamine, diisopropylamine, sodium bicarbonate or sodium carbonate, whereby the temperature is preferably between 7 0 and 150°C. The intermediate (6) is then hydrogenated to the compound of formula (7), then brominated with N-bromosuccinimide in carbon tetrachloride to produce the brominated compound (8). This latter compound is then converted into the pentavalent phosphorus compound of formula (2), e.g. using an organic phosphite such as triethyl phosphite according to the conditions of Arbusov

reaction.

When the compounds of formula I produced according to the present invention are mono-substituted naphthalene derivatives, (R 1 or R 2 =C 1 -C 15 alkyl) and more particularly the compounds of formula II, it is preferred to use methods represented by the following reaction scheme:

P = protecting group for the carbonyl function

Xi = Cl or Br.

According to this method, a coupling reaction is carried out between a 6-halo-2-tert-butyl-dimethylsilyloxy-naphthalene derivative (9) and a protected carbonyl derivative of a p-halobenzoic acid (10). According to this method, the compound 10 is converted to its magnesium, lithium or zinc form according to methods known in the literature and combined with the halogen derivative of the naphthalene compound (9) by using a transition metal or a complex thereof as a reaction catalyst.

Representative special catalysts include those made from nickel or palladium and especially compounds of NijI (NiCl2> with various phosphines, especially diphenyl-phosphine ethane.

The coupling reaction is generally carried out at temperatures between -20 and +30°C in an anhydrous solvent such as e.g. dimethylformamide and tetrahydrofuran.

Different protecting groups can be used to protect the carbonyl function of p-halobenzoic acid. However, an oxazolinyl group is preferably used.

The benzonaphthalene derivative of formula (11) is then treated with tetramethylammonium fluoride in tetrahydrofuran to form the naphthol derivatives of formula (12). This latter derivative is then converted to the trifluoromethanesulfonate derivative of formula (13), which after treatment with a suitable organocopper derivative produces according to the method described by J.E. McMurray et al, Tetrahedron Letters 24, p. 2723, 1983), the naphthalene derivative of formula (14.) substituted in the 6-position with an alkyl group. After removal of the protecting group using HC1 in aqueous solution, compounds of formula II are formed where R5=H.

To form the compounds of formula I, the method represented by the following reaction core can also be used:

Xx = Br or Cl

According to this method, a Wittig-Horner reaction is carried out between an aromatic aldehyde (1) and a pentavalent phosphorus derivative (15) in which A has the same meaning as those listed under scheme A above, and the reaction conditions are also the same . The resulting intermediate (16) is then treated with a heterocyclic halogen ester (12) according to Heck's reaction to produce the compound (18) which is then cyclized.

The coupling reaction between the aromatic aldehyde (1) and the pentavalent phosphorus derivative (15_) is preferably carried out with Wittig's reaction (A=-P(0)<+>3Br~) preferably using potassium tert.butylate in THF. This produces the stereospecific preparation of compound (16) in the Z form. The use of lithium bases such as lithium di-isopropylamide leads to E+Z mixtures of the intermediate (.16). The Heck reaction is preferably carried out between 120 and 220°C (under nitrogen), and the reaction is generally carried out in the absence of a solvent. Amines that have a high boiling point, e.g. Diazabicycloundecene (DBU) can be used as bases, but the best results are obtained using sodium carbonate with finely divided potassium, and the catalyst used is palladium(II) acetate in the presence of triphenylphosphine.

Starting from the esters and acids obtained above, it is possible to produce, according to known methods, compounds of formula I where R 3 has one of the meanings listed above.

In order to prepare the compounds according to the invention, one can first prepare intermediate products represented by the following

formula

where R 1 and R 2 have the same meaning as listed under formula I, and Y represents =0 or where K represents hydrogen, or

where X and R 5 have the same meaning as listed under formula I, and R and R' represent alkyl or together form a dioxane or dioxolane ring.

The compounds of formula I exhibit excellent activity in the inhibition test of ornithine decarboxylase in nude rats after induction by tape stripping. This experiment is considered as a measure of the activity of retinoids on cellular proliferation phenomena.

Compounds are particularly suitable for the treatment of the dermatological disorders associated with a keratinisation disorder (differentiation-proliferation) as well as dermatological diseases or other such as inflammatory and/or immunoallergic components such as mainly: Acnes vul<g>aris. comedoma or polymorph, solar senile acne and medical or professional acne, widespread and/or severe forms of psoriasis, and other keratinization disorders, and in particular ichthyosis-like diseases, Darier's disease, palmo-plantar keratodermas, leucoplasia and leuco plasia-like condition, lichen planus, any malignant or benign dermatological proliferations, severe or widespread.

They are also active in the treatment of tumours, of rheumatoid psoriasis, cutaneous or respiratory atrophies as well as in certain ophthalmic problems associated with corne-opathies.

Compared to known retinoids, the compounds according to the present invention exhibit better light and oxygen stability, which is essentially justified by the fact that they do not have easily isomerizable or oxidizable double bonds.

The compounds produced according to the present invention are generally administered in a daily dose of approx. 0.01 µg/kg to 0.1 mg/kg of body weight.

Any conventional carrier can be used as a carrier for these mixtures, and the active compound is present either in a dissolved state or in a dispersed state in said carrier.

Administration of the compounds according to the present invention can be carried out internally, parenterally, topically or ocularly. When administered enterally, the drugs can be in the form of tablets, gel capsules, lozenges, syrups, suspensions, solutions, powders, granules or emulsions.

When administered parenterally, the medicinal composition may be in the form of solutions or suspensions for perfusion or injection. When administered topically, the pharmaceutical compositions based on the compounds according to the present invention can be in the form of ointments, tinctures, creams, powders, pads, impregnated tampons, solutions, lotions, gels, sprays or suspensions.

These compositions for topical administration can be prepared either in anhydrous form or in aqueous form according to clinical indications.

When administered ocularly, the mixture is mainly present

in the form of an eye rinse.

The mixtures may also contain flavor-enhancing agents, preservatives, stabilizers, moisture-regulating agents, pH-regulating agents, osmotic pressure-regulating agents, emulsifiers, UV-A and UV-B filters, anti-oxidizing agents such as cx-tocopherol, butyl -hydroxyanisole or butylhydroxytoluene.

The following examples illustrate the preparation of the active compounds of formula I.

EXAMPLE I: The preparation of p-(6-tert-butyl-2-naphthyl)-benzoic acid

(a) 6-Bromo-2-tert-butyldimethylsilyloxynaphthene

The following substances are dissolved in 50 ml of dimethylformamide: 10g (45 mmol) 6-bromo-2-naphthol, 5.65g (55 mmol) triethylamine and 0.12g (1 mmol) 4-dimethylaminopyridine.

7.55 g (50 mmol) of tert.butyldimethylsilyl chloride is added slowly, and the resulting solution is stirred for 3 hours at room temperature. The resulting mixture is poured over 200 ml of water, acidified with concentrated HCl to a pH of approx. 1. The solution is extracted with ether (4 x 100 ml). The ether solution is washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated.

A pale yellow oil is thus obtained which is purified by elution with heptane on a short silica gel column. After evaporation of the solvent, a colorless oil is obtained which crystallizes. After drying, 13.2 g (87% yield) of the expected product is obtained. Melting point: 60-62°C.

(b) 6-(p-(4,4-dimethyl-2-oxazolinyl)-phenyl)-2-naphthol

100 ml of anhydrous THF is added to a mixture of 15.3 g (60 mmol) of p-(4,4-dimethyl-2-oxazolinyl)-bromobenzene prepared according to the method described by A. Meyers et al, JOC, 29, 2787 ( 1974), and 1.75g (70 m. at-g) of magnesium. The reaction is started spontaneously, and the reaction mixture is heated to boiling under reflux for 3 hours. After cooling, 8.16 g (60 mmol) of anhydrous zinc chloride are added, and the resulting mixture is stirred for one hour at room temperature. To the resulting white suspension is added 9.5g (28 mmol) of the substance obtained under part (a) above and 0.32g (0.6 mmol) NiCl 2 /diphenylphosphinoethane. The mixture is stirred for a further 3 hours. The reaction is stopped by the addition of a 2 M aqueous solution of ammonium chloride. The reaction medium

is then extracted with dichloromethane, and the organic phase is washed with water, then dried with magnesium sulfate. After evaporation of the solvent, an orange oil is obtained which is purified by passage through a short silica gel column using dichloromethane as eluent. After concentration of the elution solvent, 2-tert-butyldimethyl-silyloxy-6-(p-(4,4-dimethyl-2-oxazolinyl)-phenyl)naphthalene is obtained in the form of a white solid. This solid is dissolved in 50 ml of tetrahydrofuran and treated with 35 ml of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture is stirred at room temperature for 3 hours and is then poured onto water and extracted with dichloromethane. The organic phase is dried over anhydrous magnesium sulfate after being washed with water, and evaporated. An orange oil is obtained which is purified by elution over a short silica gel column using a 99:1 mixture of dichloromethane and methanol as eluent. The elution solvents evaporate to give a pale yellow oil which crystallizes. After recrystallization in hot methanol, 5.5 g of crystals are obtained in the form of faint yellow needles (64% yield). Melting point: 221-223°C.

(c) 6-(p-(3,3-dimethyl-2-oxazolin-yl)-phenyl)-2-naphthyl trifluoromethane sulfonate

To a solution of 3.03g (30 mmol) of triethylamine, 0.025g (0.2 mmol) of 4,4-dimethylaminopyridine and 5g (15.8 mmol) of the compound obtained in part (b) above, 100 ml of dichloromethane is added at 0°C, 4.89g (17.4 mmol) anhydrous trifluoromethanesulfonic acid. The resulting mixture is stirred at room temperature for 2 hours and then poured into water and acidified to pH 3 by addition of concentrated HCl.

The acidified mixture is extracted with dichloromethane. The organic phase is dried over anhydrous magnesium sulfate after being washed with water and then concentrated to give an oily solid which is purified by elution through a short silica gel column using a 3:1 mixture of hexane/dichloromethane as eluent.

After evaporating the eluents under reduced pressure and an oily, solid substance is obtained, which is recrystallized with hot cyclohexane, 3g of a white, crystalline, solid substance is obtained (42% yield). Melting point: 134-135°C.

(d) 2-(p-(6-tert.butyl-2-naphthyl)-phenyl-4,4-dimethyloxazoline

To a mixture of 0.9 g (10 mmol) of copper cyanide in tetrahydrofuran cooled to -78°C, 8.7 ml of a 2.3 molar (20 mmol) hexane solution of tert.butylitium is added slowly while stirring.

The mixture is allowed to stand until its temperature reaches 0°C. It is then cooled to -78°C where up to 1.5g (3.3mmol) of the compound obtained in part (c) above is added. The reaction mixture is again allowed to stand until its temperature reaches -20°C, at which point it is stirred for a further two hours. The reaction is stopped by adding a molar aqueous solution of ammonium chloride.

The reaction mixture is then extracted with dichloromethane and the organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure.

A pale yellow solid is obtained which is then purified by preparative HPLC (ZORBAX SIL, diisopropyl ether/iso-octane)triethylamine, 75/25/1), and gives 0.35 g (30% yield) of a faint yellow solid with a melting point of 154-159°C.

(e) p-(6-tert-butyl-2-naphthyl)benzoic acid

0.3 g (0.8 mmol) of the compound obtained in part (d) above is heated under reflux in 20 ml of a 3M HCl solution for 3 hours. A white precipitate results which is then filtered and redissolved in 20 cm 3 methonic acid NaOH at 20%. This mixture is heated under reflux for 30 minutes. The white precipitate that forms is filtered, washed with water and dried at 75°C under a vacuum for 24 hours.

0.09 g (40% yield) of the expected acid with a melting point of 310-315°C is thus obtained.

EXAMPLE 2 - Preparation of the ethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid

(a) Ethyl ester of p-(3,3-dimethoxypropyl)benzoic acid

(3.58 g of ethyl p-bromobenzoate is dissolved in 100 ml of dioxane, to which 3.83 g of triphenylphosphine, 41.00 g of acrolein dimethyl acetal, 100 g of potassium carbonate and 1.64 g of palladium (II) acetate are successively added.

The resulting mixture is heated to 110°C, with stirring

for 16 hours and then filtered over chelite. The Kelite filter is washed with 3 x 200 ml of ethyl ether and the washing medium is then dried and evaporated to give 90.37 g of a yellow oil which is dissolved in 365 ml of methanol. 1.46 g of palladium on carbon (5%) is added, and hydrogenation is carried out. When the absorption of hydrogen is

finished, the catalyst is removed by filtration on chelite. After evaporation of the methanol, the residue is chromatographed (silica column, 30 x 10 cm, eluent: 50/50 mixture of dichloromethane and hexane), and after evaporation of the solvents gives 72.77 g (79% yield) of the ethyl ester of p-(3,3-dimethoxypropyl)-benzoic acid.

(b) Ethyl ester of p-(1-diethoxyphosphoryl-3,3-dimethoxy-propyl)-benzoic acid

Dissolve 70.00 g of the product obtained under part (a) above in 1000 ml of carbon tetrachloride. 1 g of benzoyl peroxide is added and

then 49.38 g of N-bromosuccinimide are added fractionally. The resulting mixture is reheated at reflux for 45 minutes, and the succinimide that forms is removed by filtration on chelite. The solvent is evaporated and the resulting oil is dried at ambient temperature under vacuum

(1 mmHg).

The oil produced in this way is dissolved in 400 ml of triethyl phosphite

and heated to 160°C for 18 hours. The triethyl phosphite is evaporated at 120°C under vacuum in a water-jet pump. The residue is deposited on a silica column (30 x 10 cm), then eluted with a 70/30 mixture of ethyl acetate and hexane to give 46.64

g (45% yield) of the ethyl ester of p-(1-diethoxyphosphoryl-3,3-dimethoxypropyl-benzoic acid).

(c) Ethyl ester of p-[1-(2,2-dimethoxyethyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-vinyl]-benzoic acid

31.76 g of the phosphonate obtained above under part (b) is dissolved in 75 ml of tetrahydrofuran. This solution is then cooled to -78°C and a solution of lithium diisopropylamide, prepared by starting from diisopropylamine (12.5 ml) and n-butyllithium (1.6 ml in hexane) in 75 ml of tetrahydrofuran, is slowly added thereto.

To this resulting solution is added a solution of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaldehyde (16.08 g) in 50 ml of tetrahydrofuran. This mixture is first stirred for 90 minutes at -78°C and then for 90 minutes at ambient temperature.

150 ml of water is then added, and the mixture is extracted with ether (3 x 200 ml).

The organic phase is washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The dried organic phase is filtered. The solvents are evaporated. The resulting residue is chromatographed on a silica column (30 x 10 cm) using a 30/70 mixture of ethyl ether and hexane as eluent.

It is thus successively achieved:

(A) 8.02 g ethyl p-[(E)]1-2,2-dimethoxyethyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl )]-vinyl]-benzoate

with a melting point of 82°C, and

(B) 8.24 g of ethyl p-[ (Z)-[1-(2,2-dimethoxyethyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 -naphthyl)]-vinyl]-benzoate.

Yield of A + B is 50%.

(d) Ethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-anthracenyl)-benzoic acid

(i) Method I

7.02 g of the (E) isomer of the ester obtained under part (c) above are dissolved in 80 ml of dichloromethane. To this solution, 2 ml of the trimethylsilyl ester of trifluoromethanesulfonic acid is added and the mixture is stirred for 15 minutes at ambient temperature. The dichloromethane is evaporated and the remainder introduced at the top of

a short silica column (5 x 10 cm) and eluted with a 60:40 mixture of methylene chloride and heptane.

solvents, 5.65 g (94% yield) of the ethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid with a melting point of 126°C.

(ii) Method II

7.80 g of the (Z) isomer of the ester obtained under part (c) above are dissolved in 350 ml of dichloromethane. 1 ml of the trimethylsilyl ester of trifluoromethanesulfonic acid is added, and the reaction mixture is placed in a photochemical reactor. The reaction mixture is stirred for 3 hours, at ambient temperature, under irradiation (Hanovia medium pressure lamp, without filter). The dichloromethane is evaporated and the deep green residue is deposited at the top of a silica column (30 x 8 cm) and eluted with a 40:60 mixture of dichloromethane and heptane. After evaporation of the solvents, 2.67 g (40% yield) of the ethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)- benzoic acid.

EXAMPLE 3 - p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid

7.32 g of the ester obtained in example 2(d) is suspended in 400 ml of ethanol. 38 ml of 5N NaOH are added to this suspension which is then heated at 60° for 60 minutes. The ethanol is evaporated and the residue is taken up in water (500 ml) and acidified to pH 1 with 6N HCl. It is then extracted with ether (3 x 500 ml) and the organic phase is dried over MgSO 4 . After filtration and evaporation of the solvents, 30 ml of the ethyl ester by the way, and gives after filtration and filtration, 6.25 g. (92% yield) p-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2 -anthracenyl)-benzoic acid with a melting point of 282°C.

EXAMPLE 4 - p-[7-(ladamantyl)-6-methoxy-2-naphthyl]-benzoic acid methyl ester

(a) 3-(1-adamantyl)-4-methoxybenzaldehyde

11.09 g (37 mmol) of 2-(1-adamantyl)-4-bromoanisole dissolved in 85 ml of THF is added slowly to 1 g of magnesium and an iodine-

crystal. At the beginning of the reaction, the reaction mixture is heated until the reaction begins, then the rest of the solution is added in such a way that even reflux cooling is maintained. This reaction mixture is heated by reflux for 30 minutes after the addition is complete, at which time 2.70 g (37 mmol) of dry DMF is added. The reaction mixture is then stirred for 30 minutes without heating and then poured into 300 ml of a mixture of 2N aqueous HCl and dichloromethane.

The organic phase is decanted and the aqueous phase is extracted with dichloromethane. The organic extracts are combined, washed with one saturated solution of sodium bicarbonate, then with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and the solvents evaporated.

The resulting residue is purified by passage through a silica column (eluent: 60:40 mixture of dichloromethane and hexane). After evaporation of the solvents, the expected aldehyde is obtained, 8.0 g (80% yield) in the form of a light yellow powder which melts at 180°C.

(b) p-[1-(2,2-dimethoxyethyl)-2-[3-(1-adamantyl)-4-methoxyphenyl]-vinyl]-benzoic acid methyl ester

11.42 g (30.51 mmol) of the phosphonate obtained in example 2(b) is dissolved in 50 ml of THF. This solution is then cooled

-78°C and then added slowly to a solution of lithium diisopropylamide which had been prepared in the usual way

starting from 3.4 g (33.58 mmol) of di-isopropylamine and 2.1 ml (33.56 mmol) of a solution of N-butyllithium (1.6 M in hexane). The red-orange solution thus obtained is stirred in

30 minutes at -78°C and a suspension of 3-(1-adamantyl)-4-methoxybenzaldehyde obtained above under part (a) (7.5 g; 27.74 mmol) in 140 ml THF is added fractionally thereto. This addition lasts for approx. 10 minutes. The reaction mixture is then stirred first for 20 minutes at -78°C and then for 2 hours at 25°C. The mixture is poured into water and extracted 3 times with 100 ml of ethyl ether. The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and the solvents are evaporated. The residue is chromatographed on a silica column, as in example 2(c) and gives a mixture of two isomers, E and Z, of the methyl ester of p-[1-(2,2-dimethoxyethyl)-2-[3 -(1-adamantyl)-4-methoxyphenyl]-vinyl]-benzoic acid (7.5 g, 53% yield) as a partially crystallized pale yellow oil. This mixture is used as such in the continuation of the synthesis. (c) Methyl ester of p-[7-(1-adamantyl)-6-methoxy-2-naphthyl]-benzoic acid.

To 6.65 g (13.55 mmol) of the mixture obtained above under part (b) in 400 ml of dichloromethane is added 2 ml of the trimethylester of trifluoromethylsulfonic acid (TMSOTf). This mixture is irradiated with ultraviolet (UV) as in example 2(b) for 4 hours. The solvents are evaporated, then the reaction mixture is purified by passage through a silica column (eluent: 70:30 mixture of dichloromethane and hexane). The fractions containing the expected product are concentrated under vacuum. The resulting residue is filtered, washed with 300 ml of cold hexane, then dried under vacuum at ambient temperature to give 4.65 g (80% yield) of the expected product as a yellowish-white solid melting at 245°C.

EXAMPLE 5 - p-[7-(1-adamantyl)-6-methoxy-2-naphthyl]-benzoic acid

1.28 g (3 mmol) of the ester obtained in example 4 (c) is suspended in 60 ml of methanol. 6 ml of 5N NaOH are added to the suspension and the mixture is stirred while heating at reflux for 6 hours. 200 ml of methanol and 200 ml of water are then added and the resulting solution is concentrated in a manner that removes most of the methanol. 300 ml of ethyl ether and 200 ml of 2N HCl are then added and the crude acid is precipitated. The aqueous phase is recovered and 300 ml of THF is added

this. The mixture is dried over magnesium sulfate and the solvents are incorporated. The resulting solid is taken up in 300 ml of hexane. filtered and oven dried at 100°C under vacuum for 16 hours, yielding 1.16 g (98% yield) of the expected acid in the form of an off-white powder melting at 360°C.

EXAMPLE 6 - Methyl ester of p-(7-tert.butyl-6-methoxy-2-naphthyl)-benzoic acid (a) Methyl ester of p-[1-(2,2-dimethoxyethyl)-2-(3-tert.

butyl-4-methoxyphenyl)-vinyl]benzoic acid

5.49 g (28.56 mmol) of 3-tert.butyl-4-methoxy-benzoic acid aldehyde are dissolved in 100 ml of THF. The solution is cooled to -78°C and a solution of lithium diisopropylamide (34.55 mmol) in THF (50 ml), prepared as indicated above, is then added to this. The reaction is carried out as in example 4 (c). After extraction 3 times with 200 ml of ether and treatment as in example 4 (b), 5.73 g (49% yield) of the mixture of the expected E and Z esters are obtained in the form of a yellow oil.

(b) p-(7-tert-butyl-6-methoxy-2-naphthyl)-benzoic acid methyl ester

5.67 g (1374 mmol) of the mixture of the ester obtained under part (a) above are all dissolved in 400 ml of dichloromethane. 1 ml of TMSOFf is added and the mixture is irradiated with UV for 2 hours. The solvent is evaporated and the residue is chromatographed through a silica column (eluent: 60:40 mixture of CH2Cl2 and hexane) to give 3.00 g (63% yield) of the methyl ester of p-(7-tert.butyl6-methoxy-2 -naphthyl)-benzoic acid which melts at 133°C.

EXAMPLE 7 - p-(7-tert.butyl-6-methoxy-2-naphthyl)-

benzoic acid

The ester obtained in example 6(b) is dissolved in 60 ml of methanol.

6 ml of 5N NaOH are added, and the mixture is heated by refluxing for 1 hour. The methanol is then evaporated and 300

ml of water is added. This mixture is extracted 5 times with 100 ml of ether. dried over MgSO^, filtered and evaporated un-

where reduced pressure. The resulting solid is taken up in 100 ml of hexane, filtered and dried to give 0.92 g (96% yield) of the expected acid melting at 283°C.

EXAMPLE 8 - p-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]-benzoic acid methyl ester

(a) 2-[3-[3-(1-adamantyl)-4-tert-butyl-dimethylsilyloxy-phenyl]-allyl]-1,3-dioxane

33 g (72.1 mmol) of [2-(1,3-dioxan-2-yl)ethyl]triphenylphosphonium bromide are suspended in 100 ml of THF. The suspension is cooled to 0°C

and 8.5 g (75.6 mmol) of potassium terbutylate are added in small amounts

there. The mixture is allowed to stand until its temperature reaches 20°C.

It is then stirred for 1 hour at which point it boils

read to 0°C. A solution of 3-(1-adamantyl)-4-tert.butyl-dimethylsilyloxybenzaldehyde in

100 ml TMF. As soon as the addition is finished, the mixture is allowed to stand until the temperature reaches ambient temperature, at which point it is stirred for 2 hours, then poured into water and extracted with methylene chloride. The organic phase is decanted, washed with water, dried over MgSO 4 and the solvents are evaporated. The residue is purified by passage through a silica column (eluent: 50:50 mixture of CH2C12

and hexane), giving 19.4 g (95% yield) of the expected mixture containing more than 90% of isomer Z, and less than 10% of isomer E.

(b) p-[1-[(1,3-dioxan-2-yl)methyl]-2-[3-(1-adamantyl)-4-tert-butyl-dimethylsilyloxyphenyl]-vinyl]-benzoic acid methyl ester

It is added successively in a round-bottomed bottle: 19.1 g

(40.8 mmol) of the dioxane derivative prepared under part (a) for

an; 8.8 g of methyl p-bromobenzoate; 183 mg (0.8 mmol) of palladium acetate; 428 mg (1.6 mmol) of triphenylphosphine, and 11.3 g (81.6

mmol) finely divided potassium carbonate. This mixture is heated under nitrogen at 180°C for 2 hours. After cooling to ambient temperature, the resulting solid is treated with a mixture of dichloromethane and water. The organic phase is decanted, washed with water, dried over MgSO 4 , filtered and the solvents are evaporated. The resulting residue is chromatographed on a silica column (eluent: 80:20 mixture of Q^C^ and hexane) to give 9.5 g (39% yield) of the methyl ester of p-[1-[(1,3 -dioxan-2-yl)-methyl]-2-[3-(1-adamantyl)-4-tert. butyl-dimethylsilyloxyphenyl]-vinyl]-benzoic acid.

(c) p-[7-(1-adamantyl)-6-tert-butyl-dimethyl-silyloxy-2-naphthyl]-benzoic acid methyl ester

9.0 g (14.9 mmol) of the ester obtained under part (b) above are dissolved in 400 ml of dichloromethane. 2 ml of TMSOTf are added and the mixture is stirred for 3 hours and 30 minutes under nitrogen and under UV irradiation. After evaporation of the dichloromethane, the residue is deposited on a silica column and eluted with a 50:50 mixture of dichloromethane and hexane. After evaporation of the solvents, the resulting pale yellow solid is stirred in 100 ml of cold hexane. After filtration, 4.55 g (58% yield) of the expected ester are obtained in the form of a white powder which melts at 185°C.

(d) p-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]-benzoic acid methyl ester

4.55 g (8.6 mmol) of the ester obtained under part (c) above is dissolved in 30 ml of dry THF.

9.5 ml of a molar solution of tetrabutylammonium fluoride in THF is added slowly. The resulting orange-colored solution is stirred for 2.5 hours at 20°C. The THF is evaporated. After addition of water, the mixture is extracted three times with 200 ml of ethyl ether. The organic phase is washed with a saturated

solution of sodium chloride, dried over MgSO^ and then evaporated. 3.51 g (99% yield) of the expected ester in the form of a white-to-beige solid, melting at 247°C, are thus retained.

EXAMPLE 9 - p-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]-benzoic acid

1.24 g (3 mmol) of the ester obtained in example 8(c) is suspended in 60 ml of methanol. 6 ml of 5N NaOH are added and the mixture is heated at reflux for 1 hour. The methanol is evaporated and 200 ml of 2N HCl is added. The mixture is then extracted three times with 400 ml of ethyl ether. The organic phase is first washed with a saturated solution of sodium bicarbonate and then with NaCl, dried and evaporated. 1.08 g (90% yield) of the expected acid melting at 295-300°C is obtained.

EXAMPLE 10 - Methyl ester of 5-(5-6,7,8-tetrahydro~5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxyl-

acid

(a) 2-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-allyl]-1,3-dioxane

In an analogous way to the methods in example 8(a) and by

starting from 25.2 g (55 mmol) [2-(1,3-dioxan-2-yl]-triphenyl-phosphonium bromide and 10.8 g (50 mmol) 5,6,7,8-tetrahydro-5 ,5,8,8-tetramethyl-2-naphthaldehyde, after chromatography on a silica column (eluent: hexane 95%, ether 5%), 4 g (66% yield) of 2-[3-( 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-allyl]-1,3-dioxane as a yellow oil.

(b) Methyl ester of E-5-[1-(1,3-dioxan-2-yl)methyl]-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 -naphthyl)-vinyl]-2-furancarboxylic acid

9.42 g (30 mmol) of the substituted dioxane derivative obtained

front under part (a), 6.15 g (30 mmol) methyl 5-bromo-2-furoate, 135 mg (0.6 mmol) Pd(0Ac)2, 315 mg (1.2 mmol) P (C6H5 ) and 8.2 g (60 mmol) of finely divided potassium carbonate are heated at 160°C for 2 hours. 3.07 g (.15 mmol) of methyl bromofuroate, 135 mg of Pd(0Ac)2 and 315 mg of P(CgH5)3 are then added to this. Heating is continued for a further 2 hours. The reaction mixture is then cooled and purified by passage through a silica column (eluent: 80/20 mixture of dichloromethane and hexane), yielding 7.1 g (53% yield) of the expected ester melting at 123- 124°C.

(c) 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid methyl ester

7 g (16 mmol) of the ester obtained in part (b) above are dissolved in 200 ml of dichloromethane. This solution is cooled to 0°C and 1

ml TMSOTf is added to this. The mixture is allowed to stand until

the temperature is again at ambient temperature, at which point the mixture is stirred for 30 minutes. The solvent is evaporated and the residue is purified by passage through a silica column (eluent: 50/50 mixture of dichloromethane and hexane). The resulting product can be recrystallized from hexane to give 5.5 g (96% yield) of the expected ester melting at 127°C.

EXAMPLE 11 - 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid

5.2 g (14 mmol) of the ester obtained in example 10(c) is treated for 4 hours by refluxing with 200 ml of 2N methanolic NaOH. The reaction mixture is then evaporated, and the residue is taken up

in water, acidified with concentrated HCl, extracted with ether, washed with water, dried over MgSO^, evaporated and recrystallized in a 50:50 mixture of isopropyl ether and ethyl acetate.

4.6 g (93% yield of 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furan-carboxylic acid are thus obtained as melts at 229-230°C

EXAMPLE 12 - Methyl ester of 5-(5,6,7,8-tetrahydro-5,5,8,8—

tetramethyl-2-anthracenyl)-2-thiophene-carboxylic acid

(a) Methyl ester of 5-[1-[(1,3-dioxan-2-yl)methyl]-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)-vinyl]-2-thiophene-carboxylic acid

In a round-bottomed flask, introduce: 9.42 g (30 mmol) of the dioxane derivative obtained in example 10(a), 6.63 g (30 mmol) methyl 5-bromo-2-thiophene carboxylate, 135 mg Pd(0Ac)2/ 315 mg (1.2 mmol) P(CgH5)3 and 8.3 g (60 mmol) finely divided K2CO3. The mixture is heated under nitrogen at 200°C for 2 hours. 3.3 g (15 mmol) of methyl 5-bromothiophene carboxylate are then added and the mixture is heated again for 2 hours.

The reaction mixture is not perfectly purified on one silica column

(eluent: 80:20 mixture of dichloromethane and hexane)

to obtain 5.4 g of a non-separable mixture under the conditions used, of the expected product (60%) and E-2 [3-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl)-2-naphthyl]-allyl-1,3-dioxane (40%). This mixture is used as such in the continuation of the synthesis.

(b) 5-(5,6,7,8-tetrahydro-5,5,8,-tetramethyl-methyl 1-2-anthracenyl)"-2-thiophene-carboxylic acid methyl ester

The mixture obtained under part (a) above (5.2 g) is dissolved in 100 ml of dichloromethane. The resulting solution is cooled to 0°C and 500 µl of TMSOTf is added thereto. The reaction mixture is allowed to stand until its temperature reaches 20°C, at which point it is stirred for 30 minutes. The solvent is evaporated, and the resulting residue is purified by passage through a silica column (eluent: 50-50 mixture of CH 2 Cl 2 and hexane). The resulting product can be recrystallized from cyclohexane to give 2.5 g of the methyl ester of 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene-carboxyl- acid which melts at 147-148°C.

EXAMPLE 13 - 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracenyl)-2-thiophene-carboxylic acid

2.1 g (5.5 mmol) of the ester obtained in example 12(b) is treated by refluxing for 8 hours with 100 ml of 2N methanolic NaOH. The methanol is evaporated and the residue is taken up in water, acidified with concentrated HCl, extracted with ether, dried over MgSO 4 and evaporated. The residue is recrystallized in a 60:40 mixture of isopropyl ether and ethyl acetate and gives 5 g (90% yield) of 5,(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthra -cenyl)-2-thiophenecarboxylic acid which melts at 254-255°C.

EXAMPLE 14 - p-[3,4(2H)-dihydro-4,4-dimethyl-7-naphtho-[2,3-b]pyranyl]-benzoic acid methyl ester

(a) p-[1-(2,2-dimethoxyethyl)-2-(4,4-dimethyl-6-chromanyl)-vinyl]-benzoic acid methyl ester

In an analogous manner to the methods in example 4, 6.49 g (17.3 mmol) of phosphonate, prepared in example 2 (b), dissolved in THF (20 ml) are treated with a solution of lithium diisopropylamide (17.3 mmol) in THF (20 mL). A solution of 6-formylchroman is added and the resulting mixture is stirred for 2 hours at -78°C. The reaction mixture is then allowed to stand until its temperature reaches ambient temperature, at which point it is poured into water and extracted with ether. The organic phase is dried over MgSO 4 , and the solvents are evaporated. The resulting residue is chromatographed on a silica column (eluent: hexane) and gives 950 mg (15% yield) of

E, Z the mixture of the methyl esters of p[[1-(2,2-dimethoxyethyl)-2-(4,4-dimethyl-6-chromanyl)]-vinyl]benzoic acid in the form of a light yellow oil which is used as such in the continuation of the synthesis.

(b) p-[3,4(2H)-dihydro-4,4-dimethyl-7-naphtho[2,3-b)-pyranyl]benzoic acid methyl ester

950 g (2.3 mmol) of the E + Z mixture of the esters obtained before

under part (a) is dissolved in 200 ml of dichloromethane. 0.5 ml of TMSOTf is added, and the mixture is irradiated with UV. under nitrogen, with stirring. At the end of 3 hours, the solvent is evaporated. The resulting residue is chromatographed on a silica column (4 x 25 cm, eluent - 50:50 mixture of dichloromethane and hexane). After evaporation, 430 mg (54% yield) of the methyl ester of p-[3,4(2H)-dihydro-4,4-dimethyl-7-naphtho[2,3-b]pyranyl]benzoic acid are obtained which melt at 153-154°C.

EXAMPLE 15 - p-[3,4(2H-dihydro-4,4-dimethyl-7-naphtho[2,3-b]pyranyl]-benzoic acid

370 mg (1.06 mmol) of the ester obtained in example 14 (b) is suspended in 40 ml of methanol. 400 mg of NaOH pellets are added and the mixture is heated by tilapia cooling for 2 hours under stirring. The methanol is evaporated and 300 ml of water is added. After neutralization with 1N HCl, the reaction mixture is extracted with ether (3 x 300 mL). The organic phase is washed with water saturated with NaCl, dried over MgSO 4 and the solvent is evaporated to give 240 mg (68% yield) of p-[3,4(2H)-dihydro-4,4-dimethyl-7 -naphtho[2,3-b]pyronyl]benzoic acid which melts at 249-250°C.

EXAMPLE 16 - Ethylamide of 5-(5,6,7,8~tetrahydro-5,5,8,8-tetramethyl<->2-anthracenyl)-2-furancarboxylic acid

(a) 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid chloride

1.15 g (3.31 mmol) of the acid obtained in example 11 is treated with 5 ml of thionyl chloride at 40°C for 1 hour. The reaction mixture is evaporated to dryness and the residue is taken up in benzene and re-evaporated to give 1.17 g of a strong crystalline mass which is used as such in the continuation of the synthesis.

(b) Ethylamide of 5-(5,6,7,8~tetrahydro-5,5,8,8-tetra-methyl-2-anthracenyl)-2-furancarboxylic acid

200 mg (0.54 mmol) of the chloride of the acid obtained above

part (a) dissolved in 20 ml of dry CH2C12 is added to a solution of ethylamine (184 mg; 4.08 mmol) in 1 ml of CH2C12. The mixture is stirred at ambient temperature for 15 minutes. Water is added and the mixture is acidified to pH 1 with 1N HCl, extracted with CH 2 Cl 2 , washed first with a saturated solution of NaHCO 3 , then with water, dried, and the solvents evaporated. 110 mg (54% yield) of the expected amide melting at 200°C are obtained.

EXAMPLE 17 - Morpholide of 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid

To 200 mg (0.54 mmol) of the chloride of the acid obtained in exem-

pel 17(a) dissolved in 20 ml of CH2C12, 237 mg (2.72 mmol) of morpholine are added. The mixture is stirred for 15 minutes at which time water is added. The mixture is then acidified to pH 1 with IN

HCl and the organic phase are recovered. This organic phase

washed first with a saturated solution of NaHCO^ and then with water, dried over MgSO^ and evaporated. The resulting residue is purified by passage through a silica column (eluent: 9 5/5 mixture of CH 2 Cl 2 and acetone). After evaporation of the solvents, 193 mg are obtained (85%

exchange) of the morpholide of 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylic acid melting at 161°C.

EXAMPLE 18 - 2-Hydroxyethyl 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furancarboxylate

340 mg (5.4 mmol) of ethylene glycol are dissolved in 1 ml of CH2C12. To this solution is added 86 mg (1.1 mmol) pyridine and 200

mg (0.54 mmol) of the chloride of the acid obtained in Example 16(a), dissolved in 20 ml of CH 2 Cl 2 . This mixture is stirred at ambient temperature for 15 minutes at which time water is added. The resulting mixture is acidified to pH 1 with 1 N HCl, extracted with dichloromethane, washed successively with

a saturated solution of sodium bicarbonate, then with water,

dried over MgSO^ and evaporated. The resulting residue is passed through a silica column (eluent - 95/5 mixture of CH 2 Cl 2 and acetone). After evaporation of the solvents, 152 mg (71% yield) of the expected ester is obtained which melts at 14 3°C.

EXAMPLE 19 - p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzyl alcohol

300 mg (0.83 mmol) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-anthracenyl)benzoic acid obtained in example 3 above are dissolved in THF. 48 mg (1.25 mmol) of LiAlH^ are added and the mixture is first stirred for 15 minutes at ambient temperature and then for 10 minutes under reflux cooling. The mixture is allowed to stand until its temperature is again at ambient temperature. 28 µl of a saturated solution of sodium and potassium tartrate are then added. The mixture is then filtered and the THF is evaporated. The resulting residue is taken up in hexane and the precipitate that forms is filtered, yielding 167 mg (57

%'s yield) of the expected alcohol melting at 131°C.

Claims (1)

Analogous process for the preparation of a therapeutically active polycyclic aromatic compound of formula I in which X represents -CH=CH-, 0 or S, Ri and R2 independently represent hydrogen, hydroxy, straight-chain or branched alkyl having 1-6 carbon atoms, alkoxy having 1 -6 carbon atoms, 1-adamantyl, or Ri and R2 together with the adjacent carbon atoms in the naphthalene ring form a 5- or 6-membered carbocyclic ring, optionally substituted with at least one lower alkyl group or interrupted by an oxygen atom, R3 represents -CH2OH or - COR4, or -CH3 when Ri and R2 together form a 5- or 6-membered carbocyclic ring, R4 represents R5 represents hydrogen, alkyl having 1-6 carbon atoms, or monohydroxy-lower alkyl, r<1> and r" represent hydrogen or lower alkyl, or r<1> and r" together form a morpholine ring, with the proviso that Ri and R2 in formula (I) are different from hydrogen when X = S and R5 = -COOCH3, and the salts of said polycyclic aromatic derivatives with formula I, characterized by) (1) to react by a coupling reaction of the Wittig or Wittig-Horner type an aromatic aldehyde with formula wherein R 1 and R 2 have the same meaning as listed above, with a pentavalent phosphorus derivative of formula wherein X and R 5 have the same meanings as listed above, A represents (i) -PfX 1 )^-, wherein X' represents aryl, and Y represents an anion of an organic or inorganic acid or (ii) wherein Z represents alkoxy, such as ethoxy, whereby the coupling reaction is carried out in the presence of lithium diisopropylamide in tetrahydrofuran at a temperature of about -80°C, and R and R' represent lower alkyl or together form a dioxane or dioxolane ring, and (2) performing a cyclization-aromatization reaction of the product obtained in step (1) in a chlorinated solvent in the presence of an acid catalyst , preferably in dichloromethane or chloroform in the presence of sulfuric acid, paratoluenesulfonic acid or the trifluoromethanesulfonate of trimethylsilyl, said reaction possibly being carried out under UV irradiation, or b) (1) to react by means of a Wittig or Wittig-Horner reaction an aromatic aldehyde of formula with a pentavalent phosphorus derivative of formula wherein Ri and R 2 have the meanings listed in claim 1, A represents (i) -P(X')^Y~ in which X<1> represents aryl, and Y represents an anion from an organic or inorganic acid or (ii) -P(Z)2 in which Z represents alkoxy, R 0 and R' represents lower alkyl or together form a dioxane or dioxolane ring, (2) reacting the intermediate formed in step (1), which intermediate has the formula with a halogen ester of the formula wherein X and R5 have the meaning listed in claim 1, and Xi represents Cl or Br, and (3) performing a cyclization-aromatization reaction of the product obtained in step (2).