DK159967B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE STYLE BENDER DERIVATIVES - Google Patents

Description

DK 159967 B

The present invention relates to an analogous method for preparing novel stilbene derivatives of the general formula I

(R5, R6C) n In R9 "VT" "R2 5 1 9 where n represents 1 or 2 and, if n is 1, Rx and represents hydrogen, lower alkoxy or halogen; or, if n is 2, R ·

ISLAND

represents hydrogen, lower alkoxy or halogen, and R 2 represents hydrogen; R ^, R4, and R ^ represent hydrogen or lower alkyl, R ^ represents hydrogen, methyl or ethyl, and R ^ represents hydrogen, lower alkyl or halogen, and R · * represents a group - (CH-). CR 2) m R 2, where m is 0 or 1, and R 2 - represents a group R 12 0! 13 I u -CH-R13 or -C-R1 2 3 4 5 6 7 8 9 10 11 or 2-oxazolinyl or, if m is 1, also hydrogen; R 2 -2 represents hydrogen or lower alkyl; R 2 represents hydrogen, lower 3 alkyl or a group N (R 4, R 6) or -QR 4, wherein R 4 represents 4 hydrogen, lower alkyl or alkanoyl; R ^ represents hydrogen, lower alkyl or a group -OR₂ or - (CH₂) pN (R ^R₂-R); R 6 represents 6 hydrogen, lower alkyl, hydroxy-lower alkyl, phenyl-lower alkyl 7, or nitro-substituted phenyl-lower alkyl; R 1 and R 2 represent 8 hydrogen, lower alkyl or together with the nitrogen atom to which 9 is attached, a piperidino, piperazino, morpholino, thiomorpholino or pyrrolidino group; R 1 represents hydrogen or lower 11 alkyl and p represents 0, 1, 2 or 3; and ketals of compounds of formula I wherein R 2 represents a group -C (O) R 2 and R 2 represents 2

DK 159967 B

hydrogen or lower alkyl; and salts of compounds of general formula I.

As used herein, the term "lower" refers to groups of up to 6 carbon atoms.

Alkyl and alkoxy groups may be branched or unbranched, e.g. respectively. methyl, ethyl, isopropyl or 2-methylpropyl and methoxy, ethoxy or isopropoxy.

Alkanoyl groups are e.g. derived from acetic, propionic or pivalic acid or from the higher carboxylic acids with up to 20 carbon atoms, e.g. palmitic or stearic acid.

Examples of ketals are di (lower alkyl) ketals and lower alkylene numerals.

The oxazolinyl group may be substituted by one or two lower alkyl groups.

Of the halogen atoms, chlorine and bromine are preferred.

The process of the invention for the preparation of the compounds of formula I is characterized in that a compound of the general formula II

20 (R5'R ^ XX

AT'C'1 R2

is reacted with a compound of general formula III

r8

DK 159967 B

3 τ, ΙΟ> <V "|

B

wherein R 1, R 2, R 3, R 4, R 5, R 8, R 8, R 9 and n are as defined above and either A represents a triarylphosphonium alkyl group of the general formula R-CH-P [Q] 3 (YS), where R represents hydrogen, methyl or ethyl, Q represents an aryl group, Y represents the anion of an organic or inorganic acid, and B represents formyl; 10 or A represents formyl, acetyl or propionyl, and B represents a in the dialkoxyphosphinylalkyl group of the general formula R-CH-P [Z] 2 in '0 where Z represents a lower alkoxy group; to form a compound of general formula I and the group 15 R1®, if desired, functionally converted.

The aryl groups symbolized in the indicated triarylphosphonium groups with Q generally comprise all known aryl groups, with, however, especially single-core groups, e.g. phenyl or lower alkyl or lower alkoxy substituted phenyl, e.g. tolyl, xylyl, mesityl or 20 µm thoxyphenyl1.

Of the inorganic acid anions Y, the chlorine, bromine and hydrosulfate ion is preferred, and of the organic acid anions the tosyloxy ion is preferred.

The alkoxy groups symbolized in the dialkoxyphosphinylalkyl groups of formula R-CH-P [Z] o with 25 0 Z are primarily lower alkoxy groups having 1-6 carbon atoms such as methoxy or ethoxy.

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The starting compounds of formula II, if their preparation is not known or described below, can be prepared by analogy with known or by analogy with the methods described below.

Compounds of formula II wherein A is a formyl, acetyl or propionyl group and the substituents rA and R4 are hydrogen (oxo compounds of formula II) can be e.g. is prepared by subjecting an indane which is substituted in the cyclopentene ring corresponding to the desired final compound of formula I, or a correspondingly substituted tetrahydronaphthalene in the cyclohexene ring an acylation reaction. This can be done, for example. is carried out by acylating the indane or tetrahydronaphthalane derivative in the presence of a Lewis acid.

Suitable acylating agents are formaldehyde / hydrochloric acid, acetyl and propionyl halides, e.g. acetyl and propionyl chloride. Of the Lewis acids, the halides of aluminum are preferred, e.g. aluminum.

The reaction is conveniently carried out in a solvent, e.g.

nitrobenzene, or in a chlorinated hydrocarbon such as methylene chloride. In particular, the reaction temperature is between 0 and ca. + 5 ° C.

The resulting oxo compound of formula II wherein R 1 and R 2 are hydrogen is condensed according to the invention with a phosphonate of formula III, wherein B represents a dialkoxyphosphinylmethyl group, to form compounds of formula I wherein R is hydrogen.

Those for the condensation with an aldehyde of formula III, where B represents an oxo group, are required phosphonium salts of formula II, where A represents a 1- (triarylphosphonium) methyl [ethyl or propyl] group, e.g. prepared as follows:

The oxo compounds of formula II obtained in the manner described above, wherein R · · and R · are hydrogen, are reduced by approx. 0 to approx. + 5 ° C using a complex metal hydride, e.g. with sodium borohydride in an alkanol or with lithium aluminum hydride in an ether, tetrahydrofuran or dioxane, to the corresponding alcohol. The alcohol obtained is then halogenated in the presence of an amine base, e.g. pyridine, using one of the usual halogenating agents, e.g. with phosphorus oxychloride or with phosphorus tribromide. The resulting halide is 5

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is then added with a triarylphosphine in a solvent, especially with triphenylphosphine in toluene or xylene, to give the desired phosphonium salt of formula II.

Oxo compounds and phosphonium salts of formula II, wherein and are 5 and 5, respectively. alkoxy and halogen, e.g. is prepared by treating the corresponding phenol in a manner known per se by treatment with an alkylating agent, e.g. by reaction with a lower alkyl halide or with a lower alkanol in the presence of an acidic agent is converted to the corresponding alkoxy derivative of formula II.

The above mentioned phenols may e.g. prepared as follows:

The unsubstituted oxo compound of formula II is nitrated in the aromatic ring portion by treatment with a mixture of concentrated nitric acid and concentrated sulfuric acid. The nitro group 15, which is preferably in the o-position of the formyl, acetyl or propionyl group, is reduced in a catalytic manner known per se, e.g. by Raney nickel, to an amino group which is then converted into a hydroxy group via the diazonium salt in a known manner.

If the diazonium salt prepared from the amine in the heat is treated with a copper I halide, the corresponding halogen derivative of the oxo compound of formula II is obtained. By re-treating the obtained halogen derivative with a nitrating acid, in a meta position to the formyl, acetyl or propionyl group, a nitro group can be introduced which can also be converted to hydroxy or halogen in the manner described above. Upon conversion of the hydroxy group to alkoxy, as desired, similar or differentially substituted derivatives of the starting ketone of formula II are obtained.

A halogen atom in the aromatic core can, if desired, be removed again by reduction in a manner known per se.

The compounds of formula III wherein B is formyl may be prepared from 30 at the 1-position nitrosubstituted phenyl derivatives, e.g. as described in Chem. Berichten 102 (1969) on pages 2502-2507. They can also be prepared by reducing corresponding β-carboxy substituted 6

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phenyl derivatives. The reduction of a carboxyl to a formyl group may e.g. is carried out with diisobutyl aluminum hydride.

The condensation components of formula III, wherein B is a dialkoxy-phosphinylmethyl group, can be prepared from the above-described 5 compounds of formula III, wherein B represents formyl, in that the formyl group is a metal hydride, e.g. by means of sodium borohydride, is converted into a hydroxymethyl group which is then halogenated by one of the usual halogenating agents, e.g. with phosphorus trichloride, after which the resulting halogen derivative is reacted with a trialkyl phosphite, especially with triethyl phosphite, to give the desired phosphonate of formula III.

The condensation components of formula III, wherein B represents formyl or a dialkoxyphosphinylmethyl group, may also be prepared by halogenating the corresponding 1-position methylsulstituted phenyl derivative and then reacting the resulting halogenomethyl derivative with either a trialkylphosphite or hydrolyzate, then oxidized by treatment with an oxidizing agent, e.g. with manganese dioxide.

The reaction of the compounds of formulas II and III can be carried out according to known methods of Wittig or Homer reaction. Preferably, as starting compounds, such compounds of formula III are used, wherein R · *-R® does not represent any phosphorans reactive group, e.g. especially a formyl group.

As a functional derivative of a substituent R 2 in a compound of formula I, e.g. mention is made of the conversion of a carboxy group to a salt, an ester, an amide, an oxazoline derivative or to a hydroxymethyl group which in turn can be esterified or etherified; as well as hydrolysis of a carboxylic acid ester or reduction thereof to a hydroxymethyl group. The hydroxymethyl group can also be oxidized up to a formyl group. Compounds of formula I containing a formyl group may e.g. by a Wittig reaction is converted to compounds of formula I wherein a group represents - (CH = CR 2) m R 2, where m represents 1, R 2 represents H or alkyl, and R represents alkoxymethyl, alkanoyl

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loxymethyl, carboxy, alkoxycarbonyl or alkyl. All these conversions can be made in a manner known per se.

In the Wittig reaction, the components react with each other in the presence of an acid-binding agent, e.g. in the presence of a strong base 5 such as butyl lithium, sodium hydride or the sodium salt of dimethyl sulfoxide, especially in the presence of an optionally lower alkyl substituted ethylene oxide such as 1,2-butylene oxide, optionally in a solvent, e.g. in an ether such as diethyl ether or tetrahydrofuran, or in an aromatic hydrocarbon such as benzene, in a temperature range between room temperature and the boiling point of the reaction mixture.

In the Horner reaction, the components are condensed by a base and preferably in the presence of an inert organic solvent, e.g. by means of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyalkane, or by means of a sodium alcoholate in an alkanol, e.g. sodium methylate in methanol, in a temperature range between 0 ° C and the boiling point of the reaction mixture.

In some cases, it has been found appropriate to carry out the above reactions in situ, i. to bond the condensation components without isolating the phosphonium salt or phosphonate in question.

A carboxylic acid of formula I may be known per se, e.g. by treatment with thionyl chloride, preferably in pyridine, or phosphorus trichloride in toluene, is converted to the acid chloride, which upon reaction with alcohols can be converted into esters and with amines to the corresponding amide. Amides can in a manner known per se be converted to amines, e.g. by reduction with complex metal hydrides such as lithium aluminum hydride. 1

A carboxylic acid ester of formula I can be hydrolyzed in a manner known per se, e.g. in the treatment of bases, especially in the treatment of aqueous alcoholic sodium or potassium hydroxide solution in a temperature range which is between room temperature and the reaction mixture.

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boiling point of the thing, and amidating, either via an acid halide or, as described below, immediately.

A carboxylic acid ester of formula I can be converted directly to the corresponding amide, e.g. when treated with lithium amide. The lithium-5 amide is advantageously reacted at room temperature with the ester in question.

Furthermore, a carboxylic acid of formula I can be converted via the halide by reaction with 2-aminoethanol or 2-amino-2-methyl-1-propanol and subsequent cyclization into an oxazoline derivative of formula I.

A carboxylic acid or a carboxylic acid ester of formula I can be reduced in a manner known per se to form the corresponding alcohol of formula I. The reduction is advantageously carried out by a metal hydride or alkyl metal hydride in an inert solvent. As hydrides, first and foremost, mixed metal hydrides, e.g. lithium aluminum hydride or bis (methoxyethyleneoxy) sodium aluminum hydride, proved suitable. As solvents, ether, tetrahydrofuran or dioxane when lithium aluminum hydride is used, and ether, hexane, benzene or toluene when diisobutyl aluminum hydride or bis (methoxyethyleneoxy) sodium aluminum hydride is used.

An alcohol of formula I can e.g. in the presence of a base, preferably in the presence of sodium hydride, in an organic solvent such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane or dimethylformamide, or in the presence of an alkali metal alcoholate in an alcohol, in a temperature range between 0 ° C and room temperature are etherified with an alkyl halide, e.g. with methyl iodide.

An alcohol of formula I may also be esterified by treatment with an alkanoyl halide or anhydride, conveniently in the presence of a base, e.g. in the presence of pyridine or triethylamine, in a temperature range that is between room temperature and the boiling point of the reaction mixture.

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The carboxylic acids of formula I form salts with bases, especially with alkali metal hydroxides, preferably with sodium or potassium hydroxide.

The compounds of formula I occur most frequently in trans form. Possible cis moieties, if desired, can be cleaved in a manner known per se or, if desired, isomerized to the trans compounds.

The present compounds of formula I are pharmacodynamically valuable compounds. They can be used for topical and systemic therapy of benign and malignant neoplasias, premalignant lesions, and for systemic and topical prophylaxis of the aforementioned disorders.

They can also be used for topical and systematic therapy of acne, psoriasis and others with an augmentation pathologically altered dermatosis occurring as well as inflammatory and allergic dermatological disorders. The present compounds of formula I can also be used to combat mucosal diseases with inflammatory or degenerative or metaplastic changes.

The novel compounds are distinguished by known retinoids in that they are effective in extremely small amounts.

The tumor inhibitory effect of the compounds of this invention is significant. In the 20 papilloma test on mice, regression of the tumors induced with dimethylbenzantracene and croton oil was observed. The diameter of the papillomas decreases over two weeks with intraperitoneal application of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl ] -benzoic acid ethyl ester 25 at 75% at 0.2 mg / kg / week by 56% at 0.1 mg / kg / week by 48% at 0.05 mg / kg / week.

By oral administration of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid ethyl ester for mice, the diameter of the induced tumors over 2 weeks (5 single doses / week) 10

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by 63% at 0.4 mg (5 x 0.08 mg) / kg / week by 48% at 0.2 mg (5 x 0.04 mg) / kg / week by 37% at 0.05 mg (5 x 0.01 mg) / kg / week.

Furthermore, the compounds of formula I and their salts can be used for the oral treatment of rheumatic diseases, especially of those which are inflammatory and degenerative, which attack joints, muscles, tendons and other parts of the movement apparatus. Examples of such diseases are primary chronic polyarthritis, spondylarthritis ankylosing spondylitis Bechterew and arthropathia psoriatica.

For the treatment of these diseases, the compounds prepared by the method according to the invention are administered orally, conveniently in an adult dosage of about 10%. 0.01-1 mg / day, preferably 0.05-0.5 mg / day. Any overdose may manifest in the form of a vitamin A hypervitaminosis and can be readily recognized by the symptoms thereof (skin peel and hair loss).

The dose can be administered as a single dose or divided into several sub-doses.

Therefore, the compounds of formula I can be used as drugs, e.g. in the form of pharmaceutical preparations.

The preparations for systemic use may e.g. is prepared by adding a compound of formula I as an active ingredient to non-toxic, inert, per se, in such compositions, usual solid or liquid carriers.

The agents can be administered enterally, parenterally or topically. For the enteral application, the agents may e.g. used in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. For parenteral application, the agents may be used in the form of infusion or injection solutions.

The dosages at which the compounds prepared by the process according to the invention can be administered may vary according to the method and method of use and according to the needs of the patients.

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The products of the process according to the invention can be administered in amounts of approx. 0.01 to approx. 5 mg daily in one or more doses. A preferred form of administration is capsules having a content of approx. 0.1 mg to approx. 1.0 mg of active substance.

The compositions may contain inert or pharmacodynamically active additives. Tablets or granules may e.g. contain a variety of binders, fillers, carriers or diluents.

Liquid preparations can e.g. are in the form of a sterile water-miscible solution. In addition to the active substance, capsules may further contain a filler or thickener. Further, flavor enhancing additives as well as the substances used as preservatives and stabilizers, humectants and emulsifiers and salts for altering the osmotic pressure, buffers and other additives may be present.

The above-mentioned carriers and diluents may consist of organic or inorganic substances, e.g. water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic and polyalkylene glycols. It is a prerequisite that all the adjuvants used in the preparation of the preparations are non-toxic.

20 For topical use, the products in question are suitably used in the form of ointments, tinctures, creams, solutions, lotions, sprays and suspensions. Ointments and creams as well as solutions are preferred. The compositions intended for topical administration may be prepared by mixing the products prepared by the process of the invention as active ingredient with non-toxic, inert, topical treatment suitable, per se, in the usual solids or liquid carriers.

For topical use, it is appropriate to have approx. 0.001 to approx.

0.3%, preferably 0.002-0.1% solutions, and approx. 0.002 to approx.

0.5%, preferably approx. 0.002-about. 0.1% ointments, ointments or creams.

Optionally, an antioxidant 12 may be added to the compositions

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agent, e.g. tocopherol, N-methyl-γ-tocopheramine and butylated hydroxyanisole or butylated hydroxytoluene.

The process of the invention is further illustrated by the following examples: EXAMPLE 1 30.5 g of [1- (1,1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphosphonium bromide and 8 g of 4-ethoxycarbonyl-benzaldehyde are stirred after addition of 300 ml of butylene oxide for 12 hours under an inert gas atmosphere at 65 ° C. The resulting clear solution is cooled, then taken up for about 10 minutes. 500 ml of ice / water and extracted twice with hexane. The organic extract is shaken 3 times with methanol / water, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by absorption on silica gel (eluent: hexane / ether 19: 1 ratio). The p - [(E) -2- (1,1,3,3-tetramethyl-5-indanyl) propenyl] benzoic acid ethyl ester obtained by the eluate melts after recrystallization from ether / hexane at 70-71 ° C.

The [1- (1,1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphosphonium bromide used as the starting material may e.g. is prepared as follows: 1 2 3 4 5 6 7 8 9 10 11 Dissolve 87.8 g of acetyl chloride in 240 ml of nitrobenzene. In solution 2, 149.2 g of aluminum chloride are added portionwise. The mixture is cooled to 30-5 ° C and, under vigorous cooling, a solution of 195.0 g of 4 1,1,3,3-tetramethylindane in 360 ml of nitrobenzene is added dropwise. The temperature must not exceed 5 ° C. The reaction mixture is stirred for 15 hours at 0 ° G, taken up in 3 liters of ice / water and extracted with ether. The ether extract 7 is washed 2 times with 2N sodium hydroxide solution and 2 times with saturated 8 brine, dried over sodium sulfate and then evaporated 9 first in water jet vacuum and then, to remove the nitrobenzene, 10 in high vacuum. The oily (1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained as the residue boils at 100-103 ° C / 0.5 mm Hg.

i3 DK1S9967B

To 2.66 g of lithium aluminum hydride is added 40 ml of absolute ether. On cooling to 0-5 ° C, 26 g of 1,1,3,3-tetramethyl-5-indanyl-methyl ketone is added dropwise over 30 minutes. After a further 30 minutes, 25 ml of a saturated sodium sulfate solution is added dropwise to the mixture. The reaction solution is filtered. The filtrate is washed once with 1N sodium hydroxide solution and 2 times with saturated brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The oily al, 1,3,3-pentamethyl-5-indane-methanol, obtained as the residue obtained, a thin-layer chromatographically pure compound (solvent: hexane / ether 80:20 ratio), is immediately further processed as follows: 24.0 g of α-1,1,3,3-pentamethyl-5-indane-methanol is dissolved in 20 ml of absolute ether and 100 ml of absolute hexane. To the solution, after adding 2 drops of pyridine at 0-5 ° C over 30 minutes, dropwise 16.2 g of phosphorus tribromide dissolved in 80 ml of absolute hexane are added. The reaction product is taken up after an additional 1 hour stirring at 0-5 ° C in ice / water and extracted exhaustively with ether. The ether extract is washed 2 times with a saturated sodium bicarbonate solution and 2 times with brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The oily 5- (1-bromomethyl) -1,1,3,3-tetramethylindane, a thin layer chromatographically pure compound (solvent: hexane / ether in 95: 5 ratio), is immediately processed as follows: 26, Dissolve 3 g of triphenylphosphine in 120 ml of xylene. To solution 25 is added 30.9 g of 5- (1-bromethyl) -1,1,3,3-tetramethylindane dissolved in 60 ml of xylene. The mixture is heated to 100 ° C with stirring and kept at this temperature for 12 hours. The thus-formed, thickly oily, after grafting crystallizing, 1- (1,1,3,3-tetramethyl-5-indanyl) ethyl-triphenylphosphonium bromide melts after recrystallization of methylene chloride / toluene at 151-156 ° C (crystals contain 0.3 equivalent of toluene).

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Example 2 2.4 g of 1,1,3,3-tetramethyl-5-indanylmethyl ketone and 3.4 g of 4 - [(diethoxyphosphinyl) methyl] benzoic acid ethyl ester are dissolved in 7 ml of dimethylformamide. To the solution is added under argon atmosphere at room temperature and with stirring dropwise a sodium ethanolate solution prepared from 0.33 g of sodium and 7 ml of ethanol, then the mixture is stirred for 18 hours at 70 ° C. The reaction mixture is then taken up in ice / water and extracted with ether. The ether extract is washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The p - [(E) -2- (1,1,3,3-tetramethyl-5-indanyl) propenyl] benzoic acid ethyl ester, a brown oil, obtained as the residue is purified by absorption on silica gel (eluent: hexane / ether ratio 9). : 1). The ester melts after recrystallization from hexane / ether at 70-71 ° C.

EXAMPLE 3 In analogy to the process described in Example 1, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoate acid ethyl ester, m.p. 90-91 ° C, is prepared from [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide and 4- ethoxycarbonyl-benzaldehyde.

The [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide used as starting material can be prepared in an analogous manner as described in Example 1 from 5.6 7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene via (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone, via 5, 6,7,8-tetrahydro-α-5,5,8,8-pentamethyl-2-naphthalenemethanol, via 2- (bromomethyl) -5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene .

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Example 4 In analogy to the procedure described in Example 1, p - [(E) -2- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propylene benzoic acid ethyl ester, mp 97-98 ° C is prepared from 5 [1- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -ethyl] triphenylphosphonium brornide and 4-ethoxycarbonyl-benzaldehyde.

The [1- (3-methoxy-5,6,7,8-tetrahydro-5.5.8.8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide used as starting material can be prepared in an analogous manner as described in Example 1 from 3-meth 10-hexoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene via (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone , via 3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene-methanol, via 2- (1-bromethyl) -3-methoxy-5,6,7 , 8-tetrahydro-5,5,8,8-tetramethylnaphthalene.

EXAMPLE 5 In analogy to the process described in Example 1, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] - 2-Methyl-benzoic acid ethyl ester in the form of a colorless, thin-layer chromatographic pure oil, (Rf value = 0.6; hexane / 15% ether) is prepared from 20 [1- (5,6,7,8 -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide and 3-methyl-4-ethoxycarbonyl-benzaldehyde.

The 3-methyl-4-ethoxycarbonyl-benzaldehyde used as a condensation component can be prepared from 4-nitro-3-methyl-benzoic acid in an analogous manner as described for the preparation of 2-methyl-4-ethoxy-carbonyl-benzaldehyde by Huneck et al. . in Chem. Ber. 102, 2502-2507 (1969).

EXAMPLE 6 By analogy to the procedure described in Example 1, p - [(E) -2- (1,1,2,3,3-pentamethyl-5-indanyl) propenyl] benzoic acid ethyl ester,

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mp 79-80 ° C, is prepared from [1- (1,1,2,3,3-pentamethyl-5-indanyl) ethyl] triphenylphosphonium bromide and 4-ethoxycarbonyl-benzaldehyde.

EXAMPLE 7 In analogy to the process described in Example 1, p - [(E) -2- (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) propenyl] benzoic acid ethyl ester, m.p. 73 ° C is prepared from [1- (7-methoxy-1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphosphonium bromide and 4-ethoxy-carbonyl-benzaldehyde.

The starting compound used [1- (7-methoxy-1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphosphonium bromide can be, e.g. is prepared as follows: Dissolve 84.3 g (1,1,3,3-tetramethyl-5-indanyl) methyl ketone (Example 1) in 160 ml of concentrated sulfuric acid and cool to -20 ° C. At this temperature, over 10 minutes, the nitrating acid prepared from 40 ml of concentrated nitric acid and 80 ml of concentrated sulfuric acid is added. After the addition is complete, the thick porridge is immediately poured onto ice and extracted twice with ether. The ether extract is washed with sodium bicarbonate solution and brine, dried over 20 sodium sulfate and freed from solvent under reduced pressure.

The obtained (6-nitro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone melts after recrystallization from ether / hexane at 111-112 ° C.

Dissolve 75.8 g (6-nitro-1,3,3-tetramethyl-5-indanyl) methyl ketone in 1500 ml of methanol and hydrogenate with 20 g of Raney nickel for 48 hours at 45 ° C. 15 liters of hydrogen are absorbed. The reaction solution is then filtered through "Speedex" ® and the solvent removed under reduced pressure. The obtained (6-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone melts after recrystallization from ether / hexane at 161-162 ° C. 1 113.1 g (6-amino-1,3,3-tetramethyl-5-indanyl) methyl ketone is slurried in 2260 ml of 20% hydrochloric acid and cooled to 0-5 ° C. For the cold mixture

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17, a solution of 33.9 g of sodium nitrite in 115 ml of water is added dropwise over 10 minutes and stirred for 30 minutes. The cold reaction solution is then dropped over 2 hours with stirring to a solution of 243.2 g of copper I chloride in 250 ml of water and 250 ml of concentrated hydrochloric acid heated to 40-45 ° C. The reaction mixture is then cooled, taken up in ice water and extracted 3 times with methylene chloride. The organic extract is washed with brine, dried over sodium sulfate and freed from solvent under reduced pressure. The residue is purified by adsorption on silica gel (eluent: hexane / acetone 19: 1 ratio). The (6-chloro-1,3,3-tetramethyl-5-indanyl) methyl ketone obtained by the eluate melts after recrystallization from hexane / ether at 69-71 ° C.

By analogy to the process described above, (6-chloro-7-nitro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone, m.p. 119-15120 ° C, can be prepared from (6-chloro-1.1). , 3,3-tetramethyl-5-indanyl) methyl tonne; and (6-chloro-7-amino-1,3,3-tetramethyl-5-indanyl) methylcetone, m.p. 116-117 ° C, from (6-chloro-7-nitro-1,3, 3-tetramethyl-5-inda-new 1) methyl ton. 1 2 3 4 5 6 7 8 9 10 11 21.1 g (6-chloro-7-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone 2 is taken up in 48 ml of concentrated sulfuric acid and added after heating 3 to 50 ° C slowly 140 ml distilled water. To the mixture, 4 after cooling to 0-5 ° C, a solution of 5.5 g of sodium nitrite in 20 ml of water is dropped over 45 minutes. The resulting cold reaction mixture 6 is added dropwise with stirring over 2 hours to a solution of 70 ml of water and 60 ml of concentrated sulfuric acid maintained at 70 ° C. The mixture 8 is cooled, taken up in ice water and extracted 3 times with ether. The 9 organic phase is washed with brine, dried over sodium sulfate 10 and freed from solvent under reduced pressure. The residue 11 is purified by adsorption on silica gel (eluent: hexane / ether 19: 1 ratio). The (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained by the eluate melts after recrystallization from hexane / ether at 78-80 ° C.

18

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4.4 g (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone is dissolved in 10 ml of dimethylformamide. To the solution is added first 1.1 g of potassium hydroxide (dissolved in 1.2 ml of water), then 5.5 ml of methyl iodide, then stirred for 3 hours at room temperature. The reaction mixture is taken up in ice water and extracted twice with ether. The organic extract is washed several times with brine, dried over sodium sulfate and freed from solvent under reduced pressure. The prepared (6-chloro-7-methoxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone melts after recrystallization at 59-60 ° C.

25 g of (6-chloro-7-methoxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are dissolved in ca. 200 ml of methanol and hydrogenated after addition of 10 g of triethylamine and 2.5 g of 5% palladium / carbon catalyst at room temperature. During 5 hours, 1 mole equivalent of hydrogen is taken up. The reaction solution is filtered over "Speedex" ®. The filtrate is evaporated.

The residue is dissolved in water / ether and extracted several times with ether.

The organic extract is washed with brine, dried over sodium sulfate and freed from solvent under reduced pressure.

The prepared (7-methoxy-1,3,3-tetramethyl-5-indanyl) methyl ketone melts after recrystallization of hexane at 76-77 ° C.

By analogy to the procedure described in Example 1, [1- (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphosphonium bromide, m.p. 209-210 ° C, can be prepared from ( 7-Methoxy-1,3,3-tetramethyl-5-indanyl) methyl ketone via 7-methoxy-α-1,1,3,3-pentamethyl-5-indane-methanol via 5- (1-bromomethyl) ) -7-methoxy-1,3,3-tetramethyl-indane.

EXAMPLE 8 By analogy to the process described in Example 1, p - [(E) -2- (1,1,3,3-tetramethyl-5-indanyl) vinyl] benzoic acid ethyl ester, m.p. 151-152eC, can be prepared from [(1, 1,3,3-tetramethyl-5-indanyl-methyl] triphenylphosphonium chloride and 4-ethoxycarbonyl-benzaldehyde.

The starting compound used [(1,1,3,3-tetramethyl-5-indanyl) - 19

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methyl] triphenylphosphonium chloride can e.g. is prepared as follows: 34.2 g of 1,1,3,3-tetramethyl-indane, 150 ml of glacial acetic acid, 300 ml of concentrated hydrochloric acid and 77 ml of 35% formaldehyde solution are heated to 75-5 78 ° C with stirring for 2 hours. . Then a further 7.7 ml of 35% formaldehyde solution is added dropwise over 10 minutes. The reaction mixture is kept for 15 hours at the same temperature, after which it is cooled, taken up for approx. 1 liter of ice water and extracted exhaustively with toluene. The organic phase is washed neutral with water, dried over 10 sodium sulfate and evaporated under reduced pressure. The crude product obtained, a reddish oil, is distilled over a Vigreux column. The pure 5-chloromethyl-1,1,3,3-tetramethyl-indane boils at 143-146 ° C / 19 mm Hg.

By analogy to the procedure described in Example 1, [1- (1,1,3,3-tetramethyl-5-indanyl) methyl] triphenylphosphonium chloride 15 can be prepared from 5-chloromethyl-1,1,3,3-tetramethyl-indane and triphenylphosphine.

EXAMPLE 9 By analogy to the process described in Example 1, 4 '- [(E) -2- (1,1,3,3-tetramethyl-5-indanyl) propenyl] acetophenone, m.p. 130-20 131 ° C, can be prepared from [1- (1,1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphosphonium bromide and 4-acetylbenzaldehyde.

EXAMPLE 10 49 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid ethyl ester (Example 3) are dissolved in 500 ml ethanol 25 at 45 ° C and, with stirring, a solution of 20 g of potassium hydroxide in 50 ml of water is added dropwise. The mixture is stirred for 18 hours at 55 ° C, then cooled, taken up in ice / water, acidified with 3N sulfuric acid solution to pH 2 and extracted twice with methylene chloride.

The methylene chloride extract is washed with saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. On the 20th

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as the residue obtained p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid melts after recrystallization of methylene chloride / hexane at 247 DEG. 248 ° C.

EXAMPLE 11 In a suspension of 7.0 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid (Example 10) in 40 ml of absolute ether is added dropwise with addition of 1.8 ml of pyridine with stirring at 0-5 ° G 3.5 ml of thionyl chloride. The reaction solution is heated after adding 5 drops of N, N-dimethylformamide to room temperature, stirring for 18 hours and then decanting. The clear yellow solution of the acid chloride is dripped under argonate sphere in a solution of 3 ml of ethylamine in 20 ml of absolute ether. The mixture is stirred for 2 hours at room temperature, taken up in a saturated saline solution and extracted twice with ether. The ether extract is washed with a saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid monoethylamide obtained as the residue melts by recrystallization from methylene chloride / hexane at 177 -178,5eC. EXAMPLE 12 2 11.3 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 naphthyl) - 3 propenyl] benzoic acid ethyl ester (Example 3) dissolved in 20 ml of absolute 4 ether and 20 ml of absolute tetrahydrofuran are dropped at 0-5 ° C in a slurry of 1.33 g lithium aluminum hydride in 20 ml of absolute ether.

6

The reaction solution is stirred for 12 hours under an atmosphere of inert 7 gas at room temperature, then added dropwise at 0-5 ° C 5 ml of 8 saturated sodium sulfate solution and filtered over "Speedex" ®. The filtrate 9 was diluted with ether and washed once with saturated sodium hydrogen carbonate solution and twice with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)

21 DK 159967 B

thyl) propenyl] benzyl alcohol melts after recrystallization of methanol / ether at 123-124 ° C.

EXAMPLE 13 In a suspension of 6.6 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl) propenyl] benzyl alcohol (Example 12) in 10 ml of ether and 10 ml of pyridine are dropped at ca. 5 ° C with stirring 5.8 ml of acetyl chloride. The reaction mixture is stirred for 3 hours at room temperature, then taken up for approx. 100 ml of ice / water and extracted 3 times with ether. The ether extract is washed once with 1N hydrochloric acid solution and then 3 times with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The obtained p [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzyl acetate melts after recrystallization of ether at 100 101 ° C.

Example 14 5.0 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzyl alcohol (Example 12) dissolved in 25 ml of dimethylformamide, is taken up in a solution of 0.4 g of sodium hydride in 10 ml of dimethylformamide. To the mixture is added 4.3 g of methyl iodide after stirring at room temperature for 1 hour and stirring for an additional 2 hours.

The reaction solution is then taken up for approx. 200 ml of ice water and extracted 3 times with ether. The ether extract is washed 3 times with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzyl methyl ether melts after recrystallization of ether at 55-56 ° C.

EXAMPLE 15 3.48 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid (Example 10) are suspended in 12 ml of toluene. The suspension is stirred after the addition of 3.57 g of thionyl chloride in 12 22

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hours at 50 ° C and then evaporated to dryness under reduced pressure. The residue is dissolved in 6 ml of methylene chloride. The solution is dropped at 0 ° G in a solution of 2.3 g of 2-amino-2-methyl-1-propanol in 6 ml of methylene chloride. The white suspension is stirred for 2 1/2 hours at room temperature, diluted with ethyl acetate, washed 3 times with water, dried over sodium sulfate and evaporated under reduced pressure. The white crystalline residue is suspended in 20 ml of ether and added dropwise at 6 ° C 6 g of thionyl chloride. The white suspension is stirred for 30 minutes at room temperature and then cautiously added to a saturated sodium carbonate solution until the pH is approx. 9th

The now clear solution is diluted with ether. The ether phase is washed 3 times with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The 2- (p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl) -4,4- dimethyl 15-2-oxazoline melts after recrystallization of ether at 115-116 ° C.

Example 16 By analogy to the process described in Example 1, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-butenyl ] benzoic acid ethyl ester, m.p. 82-83 ° C is obtained from [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propyl] triphenylphosphonium bromide and 4-methoxycarbonyl-benzaldehyde.

The starting material used [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propyl] triphenylphosphonium bromide can be prepared in an analogous manner as described in Example 1 from 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene and propionic acid chloride.

Example 17 By analogy to the process described in Example 11, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoate

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23 Acid diethylamide, m.p. H1-112 ° C, is prepared from p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid. acid and diethylamine.

EXAMPLE 18 By analogy to the process described in Example 1, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzo -sic acid morpholide, mp 143-144 ° C is prepared from p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid and morpholine.

EXAMPLE 19 By analogy to the process described in Example 11, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoate Acidopropyl ester, m.p. 119-120 ° C, is prepared from p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] ben-15 zoic acid and isopropanol.

EXAMPLE 20 By analogy to the procedure described in Example 11, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] acid (2) diethylaminoethyl ester, m.p. 65-66 ° C, is prepared from p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 -naphthyl) propenyl] benzoic acid and 2-diethylaminoethanol.

EXAMPLE 21 6.7 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzyl alcohol (Example 12) dissolved in 100 ml of absolute ether is dropped over 10 minutes to a stirred, 0-5 ° C cooled slurry of manganese dioxide in 100 ml of absolute ether. The mixture is stirred 24

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overnight at room temperature and then filtered through Celite®. The filtrate is evaporated to dryness on a rotary evaporator. The yellowish oil crystallizes. By recrystallization of ether, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzaldehyde is obtained in the form of colorless crystals mp 140-141 eC.

EXAMPLE 22 In analogy to the process described in Example 1, 4 '- [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] acetophe non-melting point 148-149 ° C is prepared from [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide and 4- acetyl-benzaldehyde.

EXAMPLE 23

To 3.0 g of 4 '- [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] acetophenone (Example 22) dissolved in 40 ml of benzene is added a catalytic amount of p-toluenesulfonic acid and 0.6 g of ethylene glycol, and the mixture is heated in a Dean-Stark apparatus, whereupon the resulting water is continuously separated. After refluxing for 2 days, the mixture is cooled, taken up in ice / saturated sodium hydrogen carbonate solution and extracted exhaustively with ether. The ether extracts are washed 20 times with saturated brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The oily residue is purified by absorption on silica gel (eluent: hexane / ether 9: 1 ratio). The 2-methyl-2- (p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propyl) -propyl ether obtained by the eluate] phenyl) -1,3-dioxolane melts after recrystallization of ether at 122-123 ° C.

EXAMPLE 24

To 10.4 g of 4 '- [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] acetophenone (Example 22) dissolved in 100 ml absolute 25

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methanol is gently added 1.0 g sodium borohydride at 0-5 ° C. The reaction solution is stirred for 1 hour at 0 ° C and for 2 hours at room temperature, then taken up in ice / water and extracted exhaustively with ether. The ether solution is washed twice with a saturated 5 brine solution, dried over sodium sulfate and evaporated under reduced pressure. The resulting α-methyl-β - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzyl alcohol melts after crystallization of ether at 121 -123 ° C.

EXAMPLE 25 In analogy to the process described in Example 14, 1,2,3,4-tetrahydro-6 - [(E) -p- (1-methoxyethyl) -α-methylstyryl] -1,1,4,4 -tetra-methylnaphthalene, m.p. 88-89 ° C, is prepared from α-methyl-p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 naphthyl) propenyl] -benzyl alcohol.

EXAMPLE 26 By analogy to the process described in Example 13, α-methyl-β - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 naphthyl) propanyl] benzyl acetate, mp 85-86 ° C is prepared from α-methyl-p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8- too tramethyl-2-naphthyl) propenyl] -benzyl alcohol.

EXAMPLE 27 By analogy to the procedure described in Example 1, 6 - [(E) -p, ct-dimethylstyryl] -1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, m.p. 84-85 ° C , is prepared from [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide and 4-methyl-benzaldehyde.

EXAMPLE 28

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By analogy to the procedure described in Example 1, 6 - [(E) -p-isopropyl-α-methylstyryl] -1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, m.p. 86 -87 ° C is prepared from [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide and 4-isopropyl-benzaldehyde.

EXAMPLE 29 By analogy to the procedure described in Example 1, 6 - [(E) -α, 2,4-trimethylstyryl] -1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene , melting point 54-56 ° C, is prepared from [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide and 2,4-dimethyl benzaldehyde.

EXAMPLE 30 By analogy to the procedure described in Example 1, but preferably with extended reaction time, 1,2,3,4-tetrahydro-1,1,4,4-tetra-methyl-6 - [(E) -a-methyl-p-vinyls tyryl] naphthalene, m.p. 94-95 ° C, is prepared from methyl-triphenylphosphonium bromide and p - [(E) -2- (5,6,7,8-tetrahydro-5.5, 8,8-tetramethyl-2-naphthyl) propenyl] benzaldehyde (Example 21). EXAMPLE 31 2 By analogy to the process described in Example 1, but preferably 3 with extended reaction time, 1,2,3,4-tetrahydro-1,1,4,4,4 tetramethyl 6 - [(E) -α-methyl-o-allystryl] naphthalene, m.p. 64-56 ° C, is prepared from ethyl triphenylphosphonium bromide and p - [(E) - 6 2- (5,6,7,8 (tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzaldehyde (Example 21).

EXAMPLE 32

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2 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzaldehyde (Example 21) and 1.4 g of diethylphosphonoeddi dissolved in 5 ml of dimethylformamide. With stirring 5, a sodium alcoholate solution (prepared with 6.16 g sodium in 3 ml of absolute alcohol) is added at room temperature. After stirring at room temperature for 18 hours, the reaction mixture is poured onto ice cold 1N hydrochloric acid solution and extracted exhaustively with ether. The ether phases are washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is purified by adsorption on silica gel (eluent: hexane / ether 19: 1 ratio). The (E) -p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -cinnamic acid ethyl ester obtained by the eluate melts after about hexane / ether 15 stabilization at 126-127 ° C.

EXAMPLE 33 By analogy to the procedure described in Example 11, p - [(E) -2- (5,6,7,8-thea trahydro-5,5,8,8-thea tramethyl-2-naphthyl) propenyl ] benzoic acid benzyl ester, mp 113-114 ° C is prepared from p - [(E) 2-20) 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl ] benzoic acid and benzyl alcohol.

EXAMPLE 34 In analogy to the process described in Example 11, 4-nitro-benzyl-p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl) -propenyl] benzoate, mp 183-184 ° C, is prepared from p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 naphthyl) propenyl] benzoic acid and benzyl alcohol.

EXAMPLE 35

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By analogy to the procedure described in Example 11, 2-hydroxyethyl-β - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetrarnethyl-2-naph thyl) propenyl] benzoate, mp 138-139 ° C is prepared from p-5 [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ) propenyl] - benzoic acid and methylene glycol.

EXAMPLE 36

To a solution of 14.1 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] - (E) -cinnamic acid ethyl ester (Example 10 32) in 70 ml of absolute hexane is dropped at room temperature under an atmosphere of inert gas and stirring 60 ml of a 20% solution of "Dibah" (dibutyl aluminum hydride) in hexane and the mixture is stirred overnight. To the reaction solution is then added dropwise at 0-5 ° C 50 ml of methanol and filtered over "Speedex" ®. The filtrate is diluted with ether, washed once with saturated sodium bicarbonate solution and twice with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The 3-p ~ ([(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl) residue obtained as the residue 2-propen-1-ol melts after recrystallization of hexane at 109-110 ° C.

EXAMPLE 37 In analogy to the process described in Example 13, 3-p - ([(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propane) -nyl] phenyl) -2-propen-1-yl acetate, mp 109-110DC, is prepared from 3-p - ([(E) -2- (5,6,7,8-tetrahydro-5) 5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl) - (E) -2-propen-l-ol.

Claims (4)

An analogous process for the preparation of therapeutically active stilbene derivatives of the general formula I R8, R10 η7 10 5 1 (R5fR6C) n 11 R4 R , lower alkoxy or halogen; or, if n is 2, R 2 represents hydrogen, lower alkoxy or halogen, and R represents hydrogen; R 3, R 2, R 3 and R 2 represent hydrogen or lower alkyl, R 7 represents hydrogen, methyl or ethyl, R 8 and R 2 represent hydrogen, lower alkyl or halogen, and R 2 represent a group - (CH 2 R r is where a m is 0 or 1 and R 2 represents a group R 12 O -CH-R 13 or -C-R 15 or 2-oxazolinyl or, if m is 1, also hydrogen; R 2 represents hydrogen or lower alkyl; R 3 represents hydrogen, lower alkyl or a group N (R - * - 7, R * · 8) or -OR 2, wherein R 2 represents hydrogen, lower alkyl or alkanoyl; R 5 represents hydrogen , lower alkyl or a group -OR16 or - (CH2) p N (R17, R18); R16 represents hydrogen, lower alkyl, hydroxy-lower alkyl, phenyl-lower alkyl or nitrosubstituted phenyl-lower alkyl; Represents hydrogen, lower alkyl or, together with the nitrogen atom to which they are attached, a piperidino, piperazino, morpholino, thiomorpholino or pyrrolidino group; R 1 represents hydrogen or lower alkyl and p represents 0 , 1, 2 or 3; and ketals of compounds of formula I wherein R 1 represents a group -C (O) R 6 and R 2 represents hydrogen or lower alkyl; and salts of compounds of formula I, characterized in that a compound of the general formula II 10 R5'E3pfX is reacted with a compound of the general formula III wherein R · * ·, R R n, R ^, R8, R ^, R8, R ^, R ^ med and n are as defined above and either A represents triarylphosphonium alkyl group of the general formula 20 R-CH-P [Q] 3 ® Y-Ξ5, where R represents hydrogen, methyl or ethyl, Q represents an aryl group, Y represents the anion of an organic or inorganic acid, and B represents formyl; or A represents formyl, acetyl or propionyl, and B represents a in the dialkoxyphosphinylalkyl group of the general formula R-CH-P [Z] 2 vi / 25 0 where Z represents a lower alkoxy group: DK 159967B 31 to form a compound of the general formula I, and the group R 1, if desired, is functionally converted. Process according to claim 1, characterized in that a starting material is used wherein 5 R 10 represents hydroxymethyl, alkoxymethyl, alkanoyloxymethyl; carboxy, alkoxycarbonyl; formyl, alkylenedioxymethyl, alkanoyl; carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, piperidino, morpholino, thiomorpholino or pyrrolidinocarbonyl or 2-oxazolinyl. The process of claim 1, for the preparation of p - [(E) -2- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid ethyl ester, characterized in that starting compounds are used wherein R 2 -, R 2, R 5, R 6, R 8 and R 2 represent hydrogen; R8, R4 and R4 are methyl; R 2 represents carbethoxy and n represents 2. The process of claim 1 for the preparation of p - [(E) -2- (5,6,7,8 - tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzylmethyl ether, characterized in that starting compounds are used, wherein R 1, R 2, R 5, R 5, R 6, R 8 and R 2 represent hydrogen; R8, R4 and R4 are methyl; R 2 - represents carbethoxy and n represents the number 2, and the resulting p - [(E) -2- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2) (Naphthyl) propenyl] benzoic acid ethyl ester is reduced to the corresponding benzyl alcohol which is methylated.