FI68804B - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA STILBENDERIVAT - Google Patents

Description

1775 ^ 71 r «, ANNOUNCEMENT s η Ο η Λ B 11 UTLÄGG NIN GSSKRIFT 6 C'8 0 4 C Patent nyc-nr.oity 11 11 1935

Njg ^ / C 07 C 63/66, 69/767, 69/94, (51) Kv.ik // int.ci.4 1 * 3/168, 1 * 7/548, 1 * 9/794, 103 / 75, C 07 D 263/10 FINLAND-FINLAND (21) Patent application - Patentansökning 783863 (22) Application date - Ansökningsdag 15 12 78 (EN) (23) Starting date - Glltighetsdag 15.12.78 (41) Become public - Blivit offentiig 23 06 79

National Board of Patents and Registration Date of publication and publication - o, Q7 öc

Patent and registration authorities in the United States and other Member States of publicity ·> · u / · ° J

(32) (33) (31) Privilege requested — Begärd priority 22.12.77

Luxembourg (LU) 78751, 10.11.78 Switzerland

Schweiz (CH) 11590/78 (71) F. Hoffmann-La Roche 6 Co. Aktiengesel1schaft, Grenzacherstrasse 124-184, Basel, Switzerland-Schweiz (CH) (72) Peter Loel Iger, Kaiseraugst, Switzerland-Schweiz (CH) (74) Oy Kolster Ab (54) Method for the preparation of new therapeutically useful stribenzene derivatives - Förfarande för framställ nya therapeutiskt användbara sti1 benderivat

The invention relates to a process for the preparation of new therapeutically useful stilbene derivatives of the formula (I) and their salts, R1 2 x 10 r7 (R5, R6C) |

R K

. . . 1 2 wherein n = 1 or 2, and if n = 1, R and R represent hydrogen or lower alkoxy, or if n = 2, R represents hydrogen 2 3 4 5 6 or lower alkoxy and R represents hydrogen; R, R, R and R represent hydrogen 8 9 2 or lower alkyl, R represents hydrogen, methyl or ethyl, R and R represent hydrogen 68804 or lower alkyl, and R represents lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl , lower alkoxy-lower alkyl, 4,4-dimethyl-2-oxazolinyl, 2-methyl-1,3-dioxolan-2-yl or -CH = CHR 1, -COOR 4, or -c_r 13, where R ^ is hydrogen, lower alkyl, lower alkoxycarbonyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or alkanoyloxy-lower alkyl; R "is lower alkyl, benzyl, nitrobenzoyl, hydroxy-lower alkyl or di. (Lower alkyl) amino ethyl; 13 R is hydrogen, lower alkyl, lower alkylamino, di- (lower alkyl) (li) amino or morpholino This term "lower" as used herein means groups having up to 6 carbon atoms.

Alkyl and alkoxy groups may be branched or straight, for example methyl, ethyl, isopropyl or 2-methylpropyl or methoxy, ethoxy or isopropoxy.

Alkanoyl groups are, for example, derivatives of acetic, propionic or pivalic acid or also higher carboxylic acids having up to 20 carbon atoms, e.g. plamitic or stearic acid.

The preferred aryl residue is phenyl. Examples of substituted aryl radicals are hydroxy, nitro or halophenyl.

The primary aralkyl residue is benzyl.

A preferred group of compounds of formula (I) are those compounds wherein, if n = 1, R and R represent hydrogen or lower alkoxy, or if n = 2, R represents hydrogen or lower 2 3 4 5.6 alkoxy, R represents hydrogen; R, R, R and R represent hydrogen or lower alkyl, R is hydrogen, methyl or ethyl, R and R are hydrogen or lower alkyl or halogen, and R represents hydroxymethyl, lower alkoxymethyl, alkanoyloxymethyl; carboxyl, lower alkoxycarbonyl; formyl, lower alkylcarbonyl, mono-lower alkylcarbamoyl, di-lower alkylcarbamoyl, or 4,4-dimethyl-2-oxazolinyl.

The compounds of formula (I) are obtained according to the invention by reacting a compound of the general formula "• vT · (II> 3 63804) with a compound of the general formula R8 K / r1"

1 V

FT

2345689 wherein R, R ', R, R, R, R, R, R and n have the meanings given above, and either A corresponds to a triarylphosphonium alkyl group of the formula R-CH-P <fQ7g® Y®, wherein R represents hydrogen, methyl or ethyl, Q is an aryl residue and Y is an anion of an organic or inorganic acid, and B is formyl; or A is formyl, acetyl or propionyl and B represents a dialkoxyphosphinylalkyl group having a va is R-CH-P / X / ^, wherein Z represents a previous alkoxy residue; to a compound of the general formula 0 and, if desired, the residue R is converted into another functional group.

In said triarylphosphonium groups, the aryl groups denoted by Q generally include all known aryl radicals, in particular, however, monocyclic radicals, such as phenyl or lower alkyl or lower alkoxy-substituted phenyl, such as tolyl, xylyl, mesityl or p-methoxyphenyl.

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

t

In the dialkoxyphosphinylalkyl group of the formula R-CH-P / YJ, the alkoxy radicals denoted by Z are preferred lower] coke radicals having 1 to 6 carbon atoms, such as methoxy or ethoxy.

The starting compounds of formula II, if their preparation is not known or their preparation is not described later, can be prepared according to known methods or described below.

Compounds of formula II in which A corresponds to formyl, 1 2

acetyl or propionyl group, and the substituents R and R are hydrogen (oxo compounds of formula II), are obtained, for example, by acylation of an indane having the desired cyclopentene ring of formula I

4 68804, or tetrahydronaphthalene having a corresponding substituent on the cyclohexene ring. This can be done, for example, by acylating an indane or tetrahydronaphthalene derivative in the presence of a Lewis acid.

Suitable acylating agents include formaldehyde / hydrochloric acid, acetyl and propionyl halides, e.g. acetyl and propionyl chloride. Of the Lewis acids, aluminum halides, such as aluminum trichloride, are preferred. The reaction is conveniently carried out in a solvent such as nitrobenzene or a chlorinated hydrocarbon such as methylene chloride. The reaction temperature is mainly between 0 and about + 5 ° C.

. . 1 2

The resulting oxo compound of formula II in which R and R represent hydrogen is condensed according to the invention in formula III in which B

corresponds to a dialkoxyphosphinylmethyl group, with the corresponding phosphonate. . . . 1 2 sa to compounds of formula I wherein R and R are hydrogen.

The phosphonium compounds of formula II required for the condensation with an aldehyde of the formula III in which B corresponds to an oxo group in which A represents a 1- (triarylphosphonium) methyl / ethyl or propyl group can be prepared, for example, as follows:

The oxo compounds of formula II obtained above, wherein R and R represent hydrogen, are reduced at about 0 to about + 5 ° C with a metal hydride complex, e.g. sodium borohydride in alkanol or lithium aluminum hydride in ether, tetrahydrofuran or dioxane, respectively. The resulting alcohol is then halogenated in the presence of an amine base such as pyridine with a conventional halogenating agent such as phosphorus oxychloride or phosphorus tribromide, and the resulting halide is then reacted with triarylphosphine in a solvent, especially triphenylphosphine in toluene to give

Oxo compounds of the formula II and phosphonium salts in which the substituents R and R are alkoxy groups can be prepared, for example, by converting the corresponding phenol in a known manner by treatment with an alkylating agent, for example by reacting it with a lower alkyl halide or lower alkanol in the presence of an acid. to the corresponding time derivative of formula II.

5 68804

The above-mentioned phenols can be obtained, for example, as follows:

An oxo compound of formula II having no substituent on the aromatic ring moiety is nitrated by treatment with a mixture of concentrated nitric acid and concentrated sulfuric acid. The nitro group closest to the formyl, acetyl or propionyl group is catalytically reduced in a known manner, e.g. by Raney-Nikke, to an amino group which is converted to the hydroxy group in a known manner via the diazonium salt.

If the diazonium salt prepared from the amine is treated with heat with a copper (I) halide, the corresponding halogen derivative of the oxo compound of formula II is obtained. Reprocessing the resulting halogen derivative with nitric acid at the m-position relative to the formyl, acetyl or propionyl group provides a nitro group which can also be converted to a hydroxy group or halogen as described above. By converting the hydroxy group into an alkoxy group, derivatives of the starting ketones of the formula II substituted with the same or different substituents are obtained in the desired manner.

If desired, the halogen atom in the aromatic core can be removed again by reduction in a known manner.

Compounds of formula III in which B represents formyl can be prepared from phenyl derivatives having a nitro substituent in the 1-position, as described in Chem. Berichten 102 (1969) on pages 2502-2507 is described. They are also obtained by reduction of the corresponding p-carboxy-substituted phenyl derivatives. The reduction of the carboxyl group to the formyl group can be carried out, for example, with diisobutylaluminum hydride.

Condensation components of formula III wherein B represents a dialkoxyphosphinylmethyl group can be prepared from the above compounds of formula III wherein B represents formyl by converting the formyl group to a hydroxymethyl group by halogenation of a metal dihydride, e.g. sodium borohydride. e.g. with phosphorus trichloride and the resulting halogen derivative is reacted with a trialkyl phosphite, in particular triethyl phosphite, to give the desired phosphonate of formula III.

The condensation components of the formula III in which B represents formyl or a dialkoxyphosphinylmethyl group are also obtained by halogenating the corresponding phenyl derivative having a methyl substituent in the 1-position and either reacting the resulting halogenomethyl derivative and hydrogenating it with a trialkyl phosphite, by treatment with manganese dioxide.

The reaction between compounds of formulas II and III can be carried out according to known methods used in Wittig or Horner reactions. The starting materials used are mainly such. . . · 11 compounds of the formula III in which R does not correspond to any group which reacts with phosphoranes, in particular a formyl group.

1 0

Suitable functional changes to the substituent R of the compound of the formula I are, for example, the conversion of a carboxyl group into a salt, ester, amide, oxazoline derivative or hydroxymethyl group, which in turn can be esterified or etherified, as well as saponification of the carboxylic acid ester or hydrogenation.

The hydroxymethyl group can also be oxidized to a formyl group. Compounds of the formula I which may have a formyl residue can be converted, for example by the Wittig reaction, into compounds of the formula I in which R corresponds to the residue -CH = CHR, in which R can be e.g.

alkoxymethyl, alkanoyloxymethyl or alkoxycarbonyl.

All of these conversions can be performed by known methods.

In the Wittig reaction, the components are reacted with each other in the presence of an acid scavenger, e.g. in the presence of a strong base such as butyllithium, sodium hydride or the sodium salt of dimethyl sulfoxide, , such as diethyl ether or tetrahydrofuran or an aromatic hydrocarbon such as benzene at a temperature between room temperature and the boiling point of the reaction mixture.

In the Horner reaction, the components are condensed with base 7 68804 and mainly in the presence of a neutral organic solvent, e.g. using sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyalkane, or also sodium alcoholate in alkanol, e.g. sodium methylate at a temperature between 0 ° C and the boiling point of the reaction mixture.

In certain cases, it has proved expedient to carry out the above reactions in situ, i.e. coupling the condensable components together without isolating the phosphonium salt or phosphonate in question.

The carboxylic acid of the formula I can be converted in a known manner, e.g. by treatment with thionyl chloride, in particular pyridine, or with phosphorus trichloride in toluene, into an acid chloride which can be converted into esters, in the reaction with alcohols, into the corresponding amide. Amides can be converted to amines in a known manner, e.g. by reduction with metal hydride complexes such as LiAlH 2.

The carboxylic acid ester of formula I can be hydrolysed in a known manner, e.g. by treatment with alkalis, in particular by treatment with an aqueous alcoholic solution of NaOH or KOH at a temperature between room temperature and the boiling point of the reaction mixture and amidation either via an acid halide or immediately as described below.

The carboxylic acid ester of the formula I can be converted directly into the corresponding amide, for example by treatment with lithium amide. Lithium amide is reacted with that ester mainly at room temperature.

The carboxylic acid ester of formula I can further be converted via a halide by reacting it with 2-aminoethanol or 2-amino-2-methyl-1-propanol and then cyclizing to the oxazoline derivative of formula I.

The carboxylic acid or carboxylic acid ester of the formula I can be reduced in a known manner to the corresponding alcohol of the formula I. The reduction is preferably carried out with the aid of a metal hydride or an alkyl metal hydride in a neutral solvent. Particularly suitable hydrides have been mixed metal hydrides, such as lithium aluminum hydride or bis- / methoxyethyleneoxy-sodium maluminium hydride. Useful as solvents are 68804 mm. ether, tetrahydrofuran or dioxane, using lithium aluminum hydride; and ether, benzene or toluene, using diisobutylaluminum hydride or bis- / methoxyethyleneoxy-7-sodium aluminum hydride.

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

The alcohol of formula I may also be esterified by treatment with an alkanoyl halide or anhydride, conveniently in the presence of a base, for example in the presence of pyridine or triethylamine, at a temperature between room temperature and the boiling point of the reaction mixture.

The carboxylic acids of the formula I form salts with bases, in particular alkali metal hydroxides, mainly with sodium or potassium hydroxide.

The compounds of formula I are mostly obtained in trans form. The cis moieties that may be obtained can, if desired, be isolated in a known manner or isomerized to trans compounds.

The products of formula I obtained by the process are medically valuable compounds. They can be used for the local and systemic treatment of benign and malignant neoplasms, malignant lesions, as well as for the systemic and local prevention of said disease state.

They are particularly suitable for the local and systemic treatment of acne, dandruff and other slow-progressing, pre-confirmed or pre-morbid dermatological diseases, as well as inflammatory and allergic skin diseases.

In addition, the products of the process of the formula I can also be used for the control of mucosal diseases in which inflammatory or degenerative or metaplastic changes occur.

The new compounds are superior to the known retinoids in that they have an extremely low potency.

The antitumor effect of the products according to the method is significant. In a wart experiment in mice, regression of tumors induced by dimethyl 68804 libenzanthracene and croton oil is observed. Wart diameters decrease within two weeks after intraperitoneal administration of p - [(E) -2- (S, 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid ethyl ester. after administration as follows: at a dose of 0.2 mg / kg / week about 75%, at a dose of 0.1 mg / kg / week about 56%, at a dose of 0.05 mg / kg / week about 48%.

Following oral administration to mice of p-ZXE) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-7-benzoic acid ethyl ester, induced tumors diameters decrease over two weeks (5 single doses per week) as follows: at a dose of 0.4 mg (5 x 0.08 mg) / kg / week by approximately 63%, at a dose of 0.2 mg (5 x 0.04 mg) / kg / week about 48%, with a dose of 0.05 mg (5 x 0.01 mg) / kg / week about 37%. The compounds of formula I and their salts can further be used for the oral treatment of rheumatic diseases, in particular diseases such as inflammation and degeneration, which occur in the joints, muscles, tendons and elsewhere in the musculoskeletal system. Examples of such diseases are primary chronic rheumatoid arthritis, Bechterew’s stiffening spinal arthritis, and edema.

For the treatment of these diseases, the compounds of the invention are administered orally, most preferably for adults at a dose of about 0.01 to 1 mg per day, mainly 0.05 to 0.5 mg / day. A possible overdose may manifest as Vit-A vitamin poisoning and is easily detected by other symptoms (flaking of the skin, hair loss).

FI-A-62 62 280 discloses aromatic polyene compounds which have a carcinoma and skin disease-curing effect. The compounds of the present invention act at a substantially lower dose compared to these known compounds.

To demonstrate the therapeutic effect of the compounds, comparative experiments were performed using the compounds of the present invention and a compound known from the above-mentioned FI publication (9- (4-methoxy-2,3,6-trimethyl-phenyl-3,7-dimethylinone) as a reference compound. -2,4,6,8-tetraene-1-acid ethyl ester) Papillomy tumors were formed on the skin of mice by the method described in Europ. J. Cancer 10 (1074) 731. The test compounds were administered to the animals first. and intraperitoneally on day 8 of treatment as a suspension or solution in peanut oil On day 14 of treatment, the diameter of papilloma tumors from baseline (day of treatment 0) was determined.The results are summarized in the following table.

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Example 1

A mixture of 30.5 g of N- (1,3,3,3-tetramethyl-5-indanyl) ethyl] 7-triphenylphosphonium bromide and 8 g of 4-ethoxycarbonylbenzaldehyde is stirred after the addition of 300 ml of bu -ethylene oxide, protected for 12 hours under a neutral gas atmosphere at 65 ° C. The resulting clear solution is cooled, then about 500 ml of ice / water are added and extracted twice with hexane. The organic extract is shaken three times with methanol / water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified by absorption onto silica gel (eluents: hexane / ether 19: 1). The p-i (E) -2- (1,1,3,3--tetramethyl-5-indanyl) propenyl-p-benzoic acid ethyl ester obtained from the eluate melts after recrystallization from ether / hexane at 70-71 ° C.

The starting 1- (1,1,3,3-tetramethyl-5-indanyl) ethyl-7-triphenylphosphonium bromide can be prepared, for example, as follows: 87.8 g of acetyl chloride are dissolved in 240 ml of nitrobenzene. 149.2 g of aluminum chloride are added portionwise to the solution.

The mixture is cooled to 0-5 ° C and then a solution of 195.0 g of 1,1,3,3-tetramethylindan in 360 ml of nitrobenzene is added dropwise with efficient cooling. The temperature must not rise above 5 ° C. The reaction mixture is stirred for 15 hours at 0 [deg.] C., then added to 3 liters of ice / water and extracted with ether. The ether extract is washed twice with 2-norm. sodium hydroxide solution and twice saturated brine, dried over sodium sulfate and then concentrated first in water vacuum and then to remove nitrobenzene under high vacuum. The remaining oily (1,1,3,3-tetramethyl-5-indanyl) methyl ketone boils at 100-103 ° C / 0.5 torr.

13 68804 To 2.66 g of lithium aluminum hydride is added 40 ml of anhydrous ether. With cooling to 0-5 ° C, 26 g of 1,1,3,3-tetramethyl-5-indanyl-methyl ketone are added dropwise to the mixture over a period of 30 minutes. After a further 30 minutes, 25 ml of saturated sodium sulfate solution are carefully added dropwise to the mixture. The reaction solution is filtered. The filtrate is washed with 1-norm. sodium hydroxide solution and twice with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo to remove the solvent. The residual oily ° <-1,1,3,3-pentamethyl-5-indan-methanol, a compound which was homogeneous by thin layer chromatography (eluent: hexane / ether 80:20), was immediately further treated as follows: 24.0 g of Ofc-1, 1 Dissolve 3,3-pentamethyl-5-indanemethanol in 20 ml of anhydrous. ether and 100 mL of anhydrous hexane. After the addition of 2 drops of pyridine, 16.2 g of phosphorus tribromide dissolved in 80 ml of absolutely dry hexane are added to the solution at 30-5 ° C over a period of 30 minutes. After further stirring for 1 hour at 0-5 ° C, the reaction product is poured into ice / water and extracted thoroughly with ether. The ether extract is washed twice with saturated sodium hydrogen carbonate solution and twice with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo to remove the solvent. The residual oily 5- (1-bromomethyl) -1,1,3,3-tetramethylindan, a thin layer chromatographically homogeneous compound (eluent: hexane / ether 95: 5), is immediately further treated as follows: 26.3 g of triphenylphosphine are dissolved To 120 ml of xylene. To the solution is added 30.9 g of 5- (1-bromoethyl) -1,1,3,3-tetramethylindan dissolved in 60 ml of xylene. The mixture is heated to 100 ° C with stirring and allowed to stand at this temperature for 12 hours. The resulting thick oil, 1- (1,1,3,3-tetramethyl-5-indanyl) ethyl triphenylphosphonium bromide, which crystallizes after seeding, melts after recrystallization from methylene chloride-toluene at 151 DEG-156 DEG C. (crystals containing 0.3 equivalents). toluene).

68804

Example 2 2.4 g of 1,1,3,3-tetramethyl-5-indanylmethyl ketone and 3.4 g of 4-adethoxyphosphinyl) methyl] -benzoic acid ethyl ester are dissolved in 7 ml of dimethylformamide. A solution of sodium ethanolate prepared from 0.33 g of sodium and 7 ml of ethanol is added dropwise to the solution under stirring under argon at room temperature with stirring, followed by stirring for 18 hours at 70 ° C.

The reaction mixture is then added to an ice / water mixture and extracted with ether. The ether extract is washed with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. The residual p - [(E) -2- (1,1,3,3-tetramethyl-5-indanyl) propenyl] -U-benzoic acid ethyl ester, which is a brown oil, is purified by absorption onto silica gel (eluent: hexane / ether 9: 1). ). The ester melts after recrystallization from hexane / ether at 70-71 ° C.

Example 3

Working in the same manner as described in Example 1, β- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyls -triphenylphosphonium bromide and 4-ethoxycarbonylbenzaldehyde can be obtained - (') (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid ethyl ester, m.p. 90-91 ° C.

The starting 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] tri-phenylphonium bromide is obtained in the same manner as in Example 1. from 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone, 5,6,7,8-tetrahydro-O-5,5,8,8-pentamethyl-2-naphthalenemethanol, 2- (bromoethyl) -5,6,7,8-tetrahydro-5, Via 5,8,8-tetramethyl-naphthalene.

Example. 9 15 68804

Working in the same manner as described in Example 1 for β- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl? -Triphenylphosphonium bromide and 4-ethoxycarbonylbenzaldehyde p - [(E) -2- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid ethyl ester can be obtained, mp 97-98 ° C.

The starting compound 1- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl-7-triphenylphosphonium bronud is obtained in the same manner as described in Example 1 for 3-methoxy- 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-naphthalene (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ) -methyl chains are 1,3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol, 2- (1-bromoethyl) -3-methoxy -5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene.

Example 5

Working in the same manner as in Example 1, [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] triphenylphosphonium bromide and 3-methyl-9-methyl- Ethoxycarbonyl-benzaldehyde can give p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -2-methyl-benzoic acid ethyl ester as a colorless, thin layer. by layer chromatography as a homogeneous oil (Rf = 0.6; hexane / 15% ether).

The 3-methyl-U-ethoxycarbonyl-benzaldehyde used as the condensing component can be prepared from 9-nitro-3-methyl-benzohexa Posta in the same manner as in the preparation of 2-methyl-9-etck-bicarbonylbenzaldehyde as described by Huneck et al. ,

Chem. Ber. 1JT2, 2502-2507 (1996).

16 6 8 8 0 4

Example 6

In the same manner as described in Example 1, β- (1,1,2,3,3-pentamethyl-5-indanyl) ethyl 4-triphenylphosphonium bromide and 4-ethoxycarbonylbenzaldehyde can be obtained from p - [(E) -2 - (1,1,2,3,3-pentamethyl-5-indanyl) propenyl] benzoic acid ethyl ester, mp 79-80 ° C.

Example 7

In the same manner as in Example 1, [β- (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) ethyl] -triphenylphosphonium bromide and 4-ethoxycarbonylbenzaldehyde can be obtained from β- E) -2- (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) propenyl-7-benzoic acid ethyl ester, m.p. 72-73 ° C.

The starting compound [β- (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) ethyl] 7-triphenylphosphonium bromide can be prepared, for example, as follows: 89.3 g of (1,1,3,3-tetramethyl- 5-Indanyl) methyl ketone (Example 1) is dissolved in 160 ml of concentrated sulfuric acid and cooled to -20 ° C. At this temperature, nitric acid prepared from 40 ml of concentrated nitric acid and 80 ml of concentrated sulfuric acid is added over 10 minutes. At the end of the addition, the thick slurry is immediately poured onto ice and extracted twice with ether. The ether extract is washed with sodium bicarbonate solution and brine, dried over sodium sulfate and the solvent is removed in vacuo. The resulting (6-nitro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone melts after recrystallization from ether / hexane at 111-112 ° C.

75.8 g of (6-nitro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are dissolved in 1500 ml of methanol and hydrogenated under nitrogen for 48 hours at 45 ° C using 20 g of Raney nickel. 15 liters of hydrogen are absorbed. The reaction solution is then filtered through Speedex and the solvent is removed in vacuo. The resulting (6-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone melts after recrystallization from ether / hexane at 161-162 ° C.

113.1 g of (6-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are slurried in 2260 ml of 20% hydrochloric acid and cooled to 0-5 ° C. A solution of 33.9 g of sodium nitrite in 115 ml of water is added to the cold mixture over 10 minutes by dropping and then stirred for a further 30 minutes. The cold reaction solution is then added dropwise over two hours with stirring to a solution of 243.2 g of copper (I) chloride 2 in 50 ml of water and 250 ml of hydrochloric acid heated to 40-45 ° C. The reaction mixture is then cooled, poured into ice water and extracted three times with methylene chloride. The organic extract is washed with brine, dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by absorption on silica gel (eluent hexane / acetone 19: 1). The (6-chloro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eluate melts after recrystallization from hexane / ether at 69-71 ° C.

In the same manner as in the method described above, (6-chloro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone can be obtained from (6-chloro-7-nitro-1,1,3,3-tetramethyl -5-indanyl) methyl ketone, m.p. 119-210 ° C; (6-Chloro-7-nitro-1,1,3,3-tetramethyl-5-indanyl) -methyl ketone (6-chloro-7-amino-1,1,3,3-tetramethyl-5-indanyl) -methyl ketone, m.p. 116-117 ° C.

21.1 g of (6-chloro-7-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are added to 48 ml of concentrated sulfuric acid, and after heating at 50 ° C: 140 ml of distilled water is slowly added. After cooling to 0-5 ° C, a solution of 5.5 g of sodium nitrite in 20 ml of water is added dropwise over 45 minutes. The resulting cold reaction mixture is added dropwise with stirring over two hours to a solution of 50 ml of water and 60 ml of concentrated sulfuric acid, the temperature of which is maintained at 70 ° C. The mixture is cooled, then poured into ice water and extracted three times with ether. The organic phase is washed with brine, dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by absorption onto silica gel (eluent hexane / ether 19: 1). The (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eluate melts after recrystallization from hexane / ether at 78-80 ° C.

4.4 g of (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5-indanyl) -1868804 methyl ketone are dissolved in 10 ml of dimethylformamide. 1.1 g of potassium hydroxide (dissolved in 1.2 ml of water) are added to the solution, followed by 5.5 ml of methyl iodide and then stirred for three hours at room temperature. The reaction mixture is then poured into ice-water and extracted twice with ether. The organic extract is washed several times with brine, dried over sodium sulfate and the solvent is removed in vacuo. The obtained (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 about 200 ml of methanol, and after the addition of 10 g of triethylamine and 2, 5 g of 5% palladium / carbon catalyst are hydrogenated at room temperature. Hydrogen is absorbed by the molar equivalent within five hours. The reaction solution is filtered through Speedex. The filtrate is evaporated to dryness. The residue is dissolved in a water / ether mixture and extracted several times with ether. The organic extract is washed with brine, dried over sodium sulfate and the solvent is removed in vacuo. The obtained (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone melts after recrystallization from hexane at 76-77 ° C.

According to the procedure described in Example 1, 7-methoxy- <X-1,1,3,3-pentamethyl-5-indan can be prepared from (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) -methyl ketone. via methanol, 5- (1-bromoethyl) -7-methoxy-1,1,3,3-tetramethylindan [1- (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) ethyl] -triphenylphosphonium bromide, m.p. 209-210 ° C.

Example 8

According to the procedure described in Example 1, p - [(E) -2- (1,1, 3, 3-tetramethyl-5-indanyl) methyl] 7-triphenylphosphonium chloride and 4-ethoxycarbonylbenzaldehyde can be obtained from 3,3-Tetramethyl-5-indanyl) vinyl-7-benzoic acid ethyl ester, mp 151-152 ° C.

The starting compound 7- (1,1,3,3-tetramethyl-5-indanyl) -methyl-7-triphenylphosphonium chloride can be prepared, for example, as follows: 19 68804

A mixture of 34.2 g of 1,1,3,3-tetramethylindan, 150 ml of glacial acetic acid, 300 ml of concentrated hydrochloric acid and 77 ml of formaldehyde solution (35%) is heated at 75-78 ° C for two hours after stirring at room temperature. : seen. An additional 7.7 ml of 35% formaldehyde solution is then added dropwise over 10 minutes. The reaction mixture is kept at the same temperature for a further 15 hours, after which it is cooled, poured into about one liter of ice water and extracted thoroughly with toluene. The organic phase is washed with water until neutral, dried over sodium sulfate and evaporated to dryness in vacuo. The crude product obtained, reddish oil, is distilled on a Vigreux column. Pure 5-chloromethyl-1,1,3,3-tetramethylindan boils between 143-146 ° C / 19 mmHg.

According to the procedure described in Example 1, β- (1,1,3,3-tetramethyl-5-indanyl) methyl] triphenylphosphonium chloride can be obtained from 5-chloromethyl-1,3,3,3-tetramethylindan and triphenylphosphine.

Example 9

According to the procedure described in Example 1, β- (1,1,3,3-tetramethyl-5-indanyl) ethyl] -7-triphenylphosphonium bromide and 4-acetylbenzaldehyde can be obtained from 4'-Z "(E) -2- (1, 1,3,3-tetramethyl-5-indanyl) propenyl-7-acetophenone, mp 130-131 ° C.

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 at 45 ° C: to 500 ml of ethanol 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, poured into ice / water, acidified by adding 3N sulfuric acid until pH 2 and extracted twice with methylene chloride. The methylene chloride extract is washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The remaining p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid melted after recrystallization from methylene chloride / hexane. after 247-248 ° C.

20 6 8 8 0 4

Example 11

To 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) 40 ml of anhydrous ether are added, after the addition of 1.8 ml of pyridine, with stirring and dropwise addition of 3.5 ml of thionyl chloride at 0 to 5. After adding five drops of N, N-dimethylformamide to the reaction solution, heat The clear yellow acid chloride solution is added dropwise under argon to a solution of 3 ml of ethylamine in 20 ml of anhydrous ether, the mixture is stirred for 2 hours at room temperature, then poured into saturated brine, and The ether extract is washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residual p - / (E) -2- (5,6,7,8-tetrahydro-5,5,8,8 -tetramethyl-2-naphthyl) propenyl-7-benzoic acid after recrystallization from methylene chloride / hexane, ethylamide melts at 177-178.5 ° C.

Example 12

A solution of 11.3 g of p-Z '(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid ethyl ester ( Example 3) dissolved in 20 ml of anhydrous ether and 20 ml of anhydrous tetrahydrofuran, is added dropwise at 0-5 ° C to a slurry of 1.33 g of lithium aluminum hydride in 20 ml of anhydrous ether. The reaction solution is stirred for 12 hours at room temperature under the protection of neutral gas, then 5 ml of saturated sodium sulfate solution are added dropwise at 0-5 ° C and filtered through Speedex. The filtrate is diluted with ether and washed once with saturated sodium beta-carbonate solution and twice with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. The obtained ρ-ΛΕ) -? - (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzyl alcohol melts after recrystallization from methanol / ether 123-1? 4 ° C.

Example 13 6 o 8 O 4 21

To a suspension of 6.6 g of p- (f) (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzyl alcohol (Example 12 ) In 10 ml of ether and 10 ml of pyridine, add 5.8 ml of acetyl chloride to the mixture with stirring and dropwise addition.

The reaction mixture is stirred for three hours at room temperature, then poured into about 100 ml of ice / water and extracted three times with ether. The ether extract is washed once with 1-norm. with hydrochloric acid, then three times with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. The obtained p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzyl acetate melts after recrystallization from ether 100-101 ° C.

Example 14 5.0 g of p-if (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-7-benzyl alcohol (Example 12) are added, dissolved To 25 ml of dimethylformamide, to a solution of 0.4 g of sodium hydride in 10 ml of dimethylformamide. After stirring for 1 hour at room temperature, 4.3 g of sodium hydride in 10 ml of dimethylformamide are added. After stirring for 1 hour at room temperature, 4.3 g of methyl iodide are added and the mixture is stirred for a further two hours. The reaction solution is then poured into about 200 ml of ice water and extracted three times with ether. The ether extract is washed three times with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzylmethyl ether melts after recrystallization from ether at 55-56 ° C. :in.

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 To 12 ml of toluene, after adding 3.57 g of thionyl chloride, the mixture is stirred for 12 hours at 50 [deg.] C. and then evaporated to dryness in vacuo.The residue is dissolved in 6 ml of methylene chloride and the solution is added dropwise at 0 [deg.] C. to 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 21/2 hours at room temperature, diluted with ethyl acetate and washed three times with water. , dried over sodium sulphate and evaporated to dryness in vacuo, the white crystalline residue is suspended in 20 ml of ether and 6 g of thionyl chloride are added dropwise at 0 [deg.] C. The white suspension is stirred for 30 minutes at room temperature and then saturated sodium carbonate solution is carefully added until pH. is r * 9. Now the clear solution is diluted with ether is blocked three times with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. Residual 2- (pf (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl--4,4-dimethyl-2- after recrystallization from ether, oxazoline melts at 115-116 ° C.

Example 16

According to the procedure described in Example 1, β- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propyl] 7-triphenylphosphonium bromide and 4-methoxycarbonylbenzaldehyde can be obtained from 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.

The starting compound ΖΊ- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propyl-7-triphenylphosphonium bromide is obtained in the same manner as described in Example 1 using 5, 6, 7, 8 tetrahydro-5,5,8,8-tetramethyl-naphthalene and propionic acid chloride.

Example 17

According to the procedure described in Example 11, p-Z (CE) -2 - C 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-7-benzoic acid and diethylamine can be obtained from p- (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid diethylamide, m.p. 111-112 ° C.

Example 18

According to the procedure described in Example 1, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid and morpholine can be obtained. 23 6 8 8 0 4 p - [(E) -2 - C 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzoic acid morpholide, m.p. 1 43-144 ° C.

Example 19 p - [(E) -2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -7-benzoic acid and isopropanol can be obtained from p- / " (E) -2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-7-benzoic acid isopropyl ester, mp 119-120 ° C.

Example 20

According to the procedure described in Example 11, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzohepose and 2-diethylaminoethanol p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzoic acid (2) -diethylaminoethyl ester can be obtained , sp.

6 5-6 6 ° C.

Example 21

Solution of 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 anhydrous ether, is added dropwise over 10 minutes to a stirred slurry of manganese dioxide in 100 ml of anhydrous ether cooled to 0-5 ° C. Stir at room temperature overnight and then filter using Celite. The filtrate is evaporated to dryness on a rotary evaporator. The yellowish oil crystallizes. Recrystallization from ether gives p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzaldehyde as colorless crystals, m.p. is H0-141 ° C.

Example 22

According to the procedure described in Example 1, 4 '(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl) triphenylphosphonium bromide and 4-acetylbenzaldehyde can be obtained 4' - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-methyl) -propenyl] -acetophenone, m.p. 148-149 ° C.

Example 23 68804 24

To a solution of 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, a catalytic amount of p-toluenesulfonic acid and 0.6 g of ethylene glycol are added and heated in a Dean-Stark apparatus, whereby the water formed is continuously separated off After boiling for two days, cooled, ice and saturated sodium hydrogen carbonate are added. The ether extract is washed twice with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo to remove the solvent. {p - (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -phenyl '} - 1,3-dioxolane melts from ether. after recrystallization at 122-123 ° C.

Example 24

To a solution of 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 of anhydrous methanol, 1.0 g of sodium borohydride are carefully added portionwise at 0-5 ° C. The reaction solution is stirred for 1 hour at 0 ° C and for two hours at room temperature and then poured onto ice / water. The ether solution is washed twice with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo to give OC-methyl-p - / * (E) -2- (5,6,7,8-tetrahydro). -5,5,8,8-tetramethyl-2-naphthyl) propenyl-4-benzyl alcohol melts after recrystallization from ether at 121-1 23 ° C.

Example 25

According to the procedure described in Example 14, O (-methyl-p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -p-benzyl alcohol can be to give 1,2,3,4-tetrahydro-6 - [(E) -p- (1-methoxyethyl) -O-methylstyryl] -1,1,4,4-tetramethylnaphthalene, mp 88-89 ° C.

25 6 8 8 0 4

Example 26

According to the procedure described in Example 13, <* - methyl-p- (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-7-benzyl alcohol can be obtained from > (- methyl p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] -benzyl acetate, mp 85-86 ° C.

Example 27

According to the procedure described in Example 1, 6 - [(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide and 4-methylbenzaldehyde can be obtained from 6 E) -p, O- (dimethylstyryl) -1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, mp 84-85 ° C.

Example 28

According to the procedure described in Example 1, 6- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] -7-triphenylphosphonium bromide and 4-isorpopylbenzaldehyde can be obtained from 6 E) -p-isopropyl-OC-methylstyryl-7,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, m.p. 86-87 ° C.

Example 29

According to the procedure described in Example 1, E1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl.7-triphenylphosphonium bromide and 2,4-dimethylbenzaldehyde can be obtained. 6 - [(E) -OC, 2,4-trimethylstyryl] -1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, m.p. 54-56 ° C.

Example 30

However, according to the procedure described in Example 1, but preferably with a longer reaction time, from methyl triphenylphosphonium bromide and p- E (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl-7-benzaldehyde (Example 21) can be obtained 26 6 8 8 0 4 1,2,3,4-tetrahydro-1,1,4'-tetramethyl-G-Al-oC-methyl-p-vinylstyryl-7-naphthalene, m.p. 94-95 ° C.

Example 31

However, according to the procedure described in Example 1, but preferably with a longer reaction time, ethyl triphenylphosphonium bromide and p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtha) style) propenyl-7-benzaldehyde (Example 21) can give 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6 - [- (E) -O (-methyl-p-allylstyryl] -7-naphthalene), mp 64-66 ° C.

Example 32 2 g of p-Z'CE) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzaldehyde (Example 21) and 1, 4 g of diethyl phosphonoacetic acid ethyl ester are dissolved in 5 ml of dimethylformamide. To this is added a sodium alcoholate solution (prepared from 6.16 grams of sodium in 3 ml of anhydrous alcohol) with stirring at room temperature. After stirring for 18 hours at room temperature, the reaction mixture is poured into ice-cold 1-norm. hydrochloric acid and extracted thoroughly with ether. The ether phases are washed with saturated sodium hydrogen carbonate solution and brine and, after drying over anhydrous sodium sulfate, evaporated to dryness in vacuo. The residue is purified by adsorption on silica gel (eluent: hexane / ether 19: 1). (E) -p-AE) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl * 2-naphthyl) -propenyl-7-cinnamic acid ethyl acetate obtained from the eluate is various molten hexane / ether after recrystallization from 126-127 ° C.

Example 33

According to the procedure described in Example 11, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl * 2-naphthyl) -propenyl] -7-benzoic acid and benzyl chloride p-Z * (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzoic acid benzyl ester can be obtained, m.p. 113-114 C.

Example 34

According to the procedure described in Example 11, 27 6 8 8 0 4 ρ-Γ (Ε) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzoic acid and 4-Nitrobenzaldehyde can give 4-nitrobenzyl-p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl. / benzoate, m.p. 183-184 ° C.

Example 35

According to the procedure described in Example 11, p- / T (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzoic acid and methylene glycol can be to give 2-hydroxyethyl p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoate, m.p. 13 -1 39 ° C.

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] -7- (E) -cinnamic acid ethyl ester (Example 32) in 70 ml of anhydrous hexane, is added dropwise at room temperature under a protective gas atmosphere and with stirring 60 ml of a 20% solution of Dibah (hexane solution of dibutylaluminum hydride) and stirring are continued overnight. To the reaction solution is then added dropwise at 0-5 ° C 50 ml of methanol and filtered through Speedex. The filtrate is diluted with ether, washed once with saturated sodium hydrogen carbonate solution and twice with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. Obtained 3-p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl} - (E) -2-propene -1-ol melted after recrystallization from hexane at 109-110 ° C.

Example 37

According to the procedure described in Example 14, starting from 3-p - {[(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl} - (E ) -2-propan-1-ol can be obtained from 3-p - {'Z "(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtha). style propenyl} phenyl} -2-propen-1-yl acetate, mp 109-110 ° C.

Example 38 28 6 8 8 0 4

According to the procedure described in Example 14, starting from 3-Pi / '(E) -2- (5,6,6,7,8-tetrahydro-5,8,8,8-tetramethyl-2-naphthyl-2 -naphthyl) propenyl] phenyl} - (E) -2-propen-1-ol can be obtained from 3-p - {'Z' (E) -2- (5,6,7,8-tetrahydro-5,5,8 (8-tetramethyl-2-naphthyl) propenyl] phenyl] -2-propen-1-yl methyl ether, m.p. 88-90 ° C.

Claims (4)

29 6 8 8 0 4 A process for the preparation of novel therapeutically useful stilbene derivatives of the formula (I) and their salts, wherein n = 1 or 2, and in which n = 1 , R and R represent hydrogen or lower alkoxy, or if n = 2, R represents hydrogen <2 3 US 6 or lower alkoxy and hydrogen, R, R, R and R represent hydrogen 7 8 9 or lower alkyl, R / hydrogen, methyl or ethyl, R and R are hydrogen or lower alkyl, and R represents lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, H, U-dimethyl-2-oxazolinyl, 2- methyl-1,3-dioxolan-2-yl or -CH = CHR 1, -COOR 2 O 2 or -CR, wherein R is hydrogen, lower alkyl, lower alkoxycarbonyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or alkanoyloxy-lower alkyl, R is lower alkyl-5-benzyl, nitrobenzoyl, hydroxy-lower alkyl or di (lower-1,3-alkyl) aminoethyl; R is hydrogen, lower alkyl, lower alkylamino, di- (lower alkyl) amino, or morpholino; characterized in that a compound of the general formula (R5, R6C) n (II) R R3 T2 30 6 8 8 0 4 is reacted with a compound of the general formula <K10 r ^ CV "X (III) in which the symbols R ^ , R 1, R 9, R 4, R 9, R 9, R 9, R 9, R 19 and n are as defined above, and either A corresponds to a triarylphosphonium alkyl group of the formula R-CH-P / Q./ ^ Y, where R is hydrogen, methyl or ethyl, Q is an aryl residue and Y is an anion of an organic or inorganic acid, and B is formyl, or A is formyl, acetyl or propionyl, and B represents a dialkoxyphosphinylalkyl group of formula f is R-CH-PzfZi / „, where Z is a lower alkoxy residue, j 10 to a compound of general formula (I), and, if desired, the residue R is converted into another functional group. Process according to Claim 1, characterized in that a starting material is used in which R is hydroxymethyl, lower alkoxymethyl, alkanoyloxymethyl, carboxyl, lower alkoxycarbonyl; formyl, lower alkylcarbonyl, mono-lower alkylcarbamoyl, di-lower alkylcarbamoyl, or 4,4-dimethyl-2-oxazolinyl. Process for the preparation of pZ (E) -2- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-7-benzoic acid ethyl ester according to claim 1 , characterized in that 1 2 5 6 8 9 starting materials are used in which R, R, R, R, R and R denote 3 4 7 il hydrogen, R, R and R denote methyl, R denotes carbethoxy and n is 2. Process for the preparation of pZ "(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzylmethyl ether according to Claim 1, characterized in that 125689 34 starting materials in which R, R, R, R, R and R are hydrogen, R, R and 7 11 ... R are methyl, R is carbethoxy and n is 2, are reduced by the resulting pZ ~ (E) -2- ( 3-Methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl / benzoic acid ethyl ester to the corresponding benzyl alcohol and methylated to this 31 6 8 80 4 Förfarande för framställning av nya therapeutically anthers are formulated with formulas (I) and other forms (-L R- R7 (, R ^ (I) \ n R4 / \ r3 | * R 2 R • · 1 2 l vilken formula n = 1 or 2, och lfall n = 1, betyder R and R derivative or alkoxy, eller l = 2, betyder R derivative or R 2 2 US 6 alkoxy and R derivative; R, R, R and R betyder or alkyl alkyl, 7 8 9 10 R content, methyl or ethyl, R and R content of alkyl, och R betyder alkyl, hydrox 1-la-alkyl, alkanoyloxy-la-alkyl, la-alkoxy-la-alkyl-1,4,4-dimethyl-2-oxazolinyl, 2-methyl-1,3-dioxolan-2-yl or group -CH = CHR'1 '^, -COOR ^ 2, 0 "13 11 or -CR, colors R är statement, l-alkyl, l-real alkoxycarbonyl, hydroxy-l-alkyl, l-alkoxy-l-alkyl-alkyl or alka- 12 noyloxi-lägre-alkyl; R 1 is alkyl, benzyl, nitrobenzoyl, hydroxy; 13-Roxy-alkyl-alkyl or di (alkyl-alkyl) aminoethyl; R är väte, lägre-alkyl, lägre-alkyl-amino, di- (lägre-alkyl) amino, eller morfc-Lino, kännetecknat därav, att man omsätter en förening med den allmänna formuleln (II) κΛ'7 τΓ ^ 1