CS201509B2 - Method of producing substituted phenyl nonatetraene compounds - Google Patents

Abstract

Novel polyene compounds of the general formula <IMAGE> in which R1 and R2 denote chlorine or bromine and R3 denotes alkoxymethyl, carboxyl, alkoxycarbonyl or mono- or di-lower alkyl carbamoyl, and salts thereof are prepared by lengthening the side chain, containing a formyl or triarylphosphonium-methyl group in a benzene derivative appropriately substituted in the 2-, 4-, 5- and 6-position. A carboxylic acid of formula I may be esterified or converted to an amide. A carboxylic acid ester of formula I may be hydrolysed. A carboxylic acid or a carboxylic acid ester of formula I can be reduced to the alcohol of formula I, wherein R3 represents hydroxymethyl. The compounds of formula I possess anti-neoplastic and tumour-inhibiting activity.

Description

(54) A method for producing substituted phenylnunatetraene compounds

The present invention relates to a process for the preparation of novel substituted phenyl-on-tetraene compounds of formula I,

in which they mean

R 1 and R 2 are chlorine or bromine;

R 3 is hydroxymethyl, C 1 -C 6 alkoxymethyl, carboxyl, C 1 -C 6 alkoxycarbonyl, or mono- or di (lower) a (C 1 -C 6) lower alkyl; m ^ c ^ c ^r y ^ v ^ ou group having 1 to 6 carbon alkyl, and salts of these compounds ·.

The above alkoxymethyl radicals and alkoxycarbonyl radicals are to be understood as meaning those radicals containing alkoxy groups containing up to 6 carbon atoms. These groups may have a straight chain branched chain such as methoxy, ethoxy or isopropoxy.

A carbamyl group is a carbamoyl group which is monosubstituted or substituted by straight or branched lower alkyl radicals having 1 to 6 carbon atoms, for example methyl, ethyl or isopropyl, such as methylcarbamoyl, ethylcarbamoyl or diethylcarbam.

Compounds which can be prepared according to the invention include:

9- (2,6-Chloro-4-methoxy-5-methylphenyl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid;

9- (2,6-Chloro-4-methoxy-5-methyl-phenyl) -4-N-methyl-4,6,6-tetraenoic acid ethyl ester;

9- (2,6-dibromo-4-methoxy-5-methylphenyl) -3,7-dimethyl-amino-2,4,6,8-tetraenoic acid ethyl ester;

9- (2,6-di-chloro-4-methoxy-5-methoxy-phenyl) -3,7,4,4,4,4,4,4,4,4,4,4,5,5,8-tetraacetic acid ethylamine;

9- (2,6-dichloг-4-methoxy --- methylfennl) -3 ₁ 7-Dimethyl-non-tetrann 2,4,6,8-l-AD;

9- (2,6-dichloro-4-methoxy-5-methylphenyl) -3,7-dimethylamino-2,4,6,8-tetraen-1-ol methyl ether.

The novel polyene compounds of formula (I) according to the invention are prepared by converting them to a compound of formula (II)

acts with a compound of formula III,

m = 0 and n = 1, or m = 1 and n = 0, one of both A and B is a formyl group and the other is a triarylphosphonium methyl group of the formula —CH2 —P [X] 3 © Y © in which

X is an aryl group and

Y is an anionic organic or inorganic acid, the radicals R 1 and R 2 are as defined above, -a.

R4 --jestliže · B represents a formyl group, - · means Alko ^^^ j ^ i ^ t H ⁱ yl group having 1 to 6 carbon · · atoms "alkoxycarbonyl, carboxyl, alkoxycarbonyl. a group having 1 to 6 carbon atoms in the alkoxy moiety or a mono- or di (lower jalkylcarbamoyl) group having 1 to 6 carbon atoms in the alkyl radicals, and

Ro, when B represents a triarylphosphonium methyl group, represents a carboxyl group, a (C1-C6) alkoxycarbonyl group or a mono or di (lower C1-C6-alkylcarbamoyl group) in the presence of an acid-binding agent or alkylene oxide at temperatures between room temperature and the boiling point of the reaction mixture, whereupon the resulting acid is optionally converted into a salt or the carboxylic acid of formula I is converted to a carboxylic acid ester of formula I or an amide of formula I or a carboxylic acid of formula I or an amide of formula I or a carboxylic acid of formula I or a carboxylic acid ester of formula I is reduced to the corresponding alcohol of formula I and this is optionally etherified.

The triaryl-4-phenyl-methyl group of the formula -CH 2 -P [X] with Y-containing aryl groups denoted as aryl groups contains all known aryl radicals, in particular mononuclear radicals such as phenyl or phenyl substituted with aryl groups. lower alkyl radicals, optionally lower alkoxy radicals, such as tolyl, xylyl, mesityl or p-methoxyphenyl. Of the inorganic antones of the acid Y, the chloride, bromide and iodide ion or hydrosulphate ion are preferred, and the organic acid anions are preferably the tosyloxy group in the form of an ion.

The starting materials of formulas II and III are in part novel compounds. These compounds can be obtained, for example, as follows:

Compounds of formula (II) wherein m = 0 and A is irarylphosphonium. a group of formula IIIa, can be obtained, for example, by reacting the appropriately substituted benzene in the presence of hydrogen halide, for example in the presence of concentrated hydrochloric acid, optionally in a solvent, in particular glacial acetic acid, with formaldehyde and the substituted benzyl in which m = 0 and A represents a halomethyl group (Ile)] is described in a manner known per se with a triarylphosphine in a solvent, in particular triphenylphosphine in toluene or benzene.

The methoxy group present in the above-substituted benzene can be introduced, for example, by methylation of the hydroxy group. Thus, for example, the corresponding phenol is reacted, preferably in a solvent, for example an alcohol, and in the presence of a base, a portion of potassium carbonate, with methyl halide, for example methyl iodide or dimethyl sulfate.

Compounds of formula II in which m = 1 and 'A is trarylphotonium methyl group [IIb] can be obtained, for example, as follows:

The appropriately substituted benzene is first subjected to a formylation reaction by, for example, treating the starting material with a formylating action. This can be accomplished, for example, by formulating the starting material in the presence of a Lew's acid. Possible formulating agents are, in particular, the following substances: formic acid esters, formyl chloride and of methyl formamides. Among the Lewis acids, particularly suitable are halogen, zinc, aluminum, titanium, tin and iron, zinc chloride, aluminum chloride, titanium tetrachloride, tin tetrachloride and ferric chloride, as well as halides of inorganic and organic acids, such as e.g. - phosphoric acid ion and. methanesulfonyl chloride ¹⁰ .

If the formulating agent is used in excess, the molding may be carried out optionally without the addition of additional solvent. However, it is generally recommended to carry out the reaction in an inert solvent such as nitrobenzene or a chlorinated hydrocarbon,

201309 as in methylene chloride. The reaction temperature may be between 0 ° C and the boiling point of the reaction mixture.

The substituted benzaldehyde of formula IIc obtained can then be extended to a temperature known per se by condensation with acetone at low temperature, for example in the range of from 0 to 30 ° C, in the presence of alkali, for example in the presence of dilute aqueous sodium hydroxide solution. substituted phenylbut-3-en-2-one, which can then be converted in a manner known per se by an organometallic reaction, for example by the Grignard reaction by addition of acetylene to the appropriately substituted phenyl-3-methyl-3-hydroxypenta-4-en- tench. The tertiary acetylene carbinol obtained is then partially hydrogenated in a manner known per se with the aid of a partially deactivated noble metal catalyst (Modeller catalyst). The resulting tertiary ethylene carbinol can then be converted under allyl rearrangement by treatment with a triarylphosphine, in particular triphenylphosphine, in the presence of a mineral acid, for example in the presence of a hydrogen halide such as hydrogen chloride or hydrogen bromide, or in the presence of a sulfuric acid in a solvent such as benzene to the desired phosphonium salt. of formula IIb wherein m = 1. The tertiary ethylenecarbinol can be further halogenated. is converted to a halide of formula II in which m = 1 and A is a halomethyl group [Uf] by treatment of a triarylphosphine, for example triphenylphosphine, with the corresponding phosphorus salt of formula IIb in which m = 1.

Compounds of formula II in which m = 0 and A is a formyl group [IIc] can be prepared, for example, by formulating the appropriately substituted benzene as described above. Starting from a substituted benzene, the directly substituted benzaldehyde of formula IIc is thus obtained.

Compounds of formula (II) in which m = 1 and A is a formyl group [IId] can be prepared, for example, by substituting a substituted lenyl-but-3-en-2-one, as described above. in the preparation of the compounds of formula IIb, it reacts according to Wittig with ethoxycarbonylmethylenetrifenylsphosphorus. The substituted phenyl-3-methylpenta-2,4-denoic acid ethyl ester obtained is then reduced in the cold with a mixed metal hydride, in particular lithium aluminum hydride, in an organic solvent, for example in ether or tetrahydrofuran, to substituted lenyl-3-methyl: ιenta - 2 ₁ 4-dien-l-nL resulting alcohol is then action-da-ke agents such mangamčitého oxide is oxidized in an organic solvent such as acetone or methylene chloride · the temperature range between 0 ° ^C and the boiling point of the reaction mixture to the desired substituted phenyl-3-methyl-penta-2,4-dien-1-al of formula IId.

Compounds of formula III in which n = 0 and B are a triarylphosphonium methyl group [IHa] can be prepared in a simple manner by converting an optionally esterified 4-halophen-3-methylthrothioic acid or an esterified 4-haloalkylene group. The ethyl alcohol is reacted with a solvent, in particular triphenylphosphine, in toluene or benzene, in reaction with the alkyl alcohol.

Compounds of formula III in which η = 1 and B represent a triaryiphosphonium mercuryl group [IHb] can be obtained, for example, by reducing the formyl group of the aldehyde of formula III in which η = 1 and B represent a formyl group (IIld), a metal such as sodium borohydride in an alcohol such as ethanol or isopropanol to a hydroxymethyl group. The alcohol obtained can be halogenated using the customary halogenating agent, for example phosphorus pentoxide, and the resulting 8-halogens, 7-dimethylethyl) -ta, 2,4,6-rien-1-carboxylic acid, halogen III. wherein η = 1 and B · · represents a halomethyl group [IIIf] or a derivative thereof with a solvent, in reaction, in particular with triphenylphosphine in toluene or benzene, to form the desired phosphonium salt of formula IIIb.

The compounds of the formula III in which n = 0 and B represent a formyl group [IIIc] can be obtained, for example, by the oxidative cleavage of the optionally tartiated tartaric tartaric acid, for example by treatment with lead acetate at room temperature. an organic solvent such as benzene. The obtained glyoxalic acid derivative is then condensed with propionaldehyde at an elevated temperature, for example in a temperature range of between 60 and 110 ° C, in a manner known per se, in particular in the presence of an amine, to cleave water to give the desired 3-formylcrotonic acid derivative. .

Compounds of formula III, in which η = 1 and B is a formyl group [IIId], can be prepared, for example, by the reaction of 4,4-dimethyloxy-3-methylbut-1-III-III in the cold, preferably at -10 ° C. to -20 ° C, in the presence of a tertiary amine, such as pyridine, is phosgene, and the resulting 2-formyl-4-chloro-buti-2-ene is coupled by a Wittig reaction with optionally tsterilized 3-formyl cronic acid or esterified 3-formylcrotyl alcohol. to form the desired aldehyde of formula IIldh

According to the invention, in reaction:

- phosphonium salts with aldehydes. or IIIc or the phosphonium salts with aldehydes of formula IIIa or IIIb of formula IId or IIc.

According to the procedure for the Wittig reaction, the components in the presence of an acid binding agent, for example in the presence of an alkali metal alkoxide such as sodium methoxide, or in the presence of an optionally alkyl-substituted alkylene oxide, in particular in the presence of ethylene oxide or 1,2-butylene oxide a solvent such as a chlorinated hydrocarbon such as methylene chloride or also dimethylformamide in the reaction ranges from room temperature to the boiling point of the reaction mixture.

In certain cases, it has proven expedient to carry out the above reactions in situ, ie to condense the condensation components without isolating the corresponding phosphonium salt.

The carboxylic acid of formula I can be converted into the acid chloride in a known manner, for example by treatment with thionyl chloride, preferably pyridine, whereby the acid chloride can be converted by reaction with an alkanol to an ester or by reaction with an alkylamine to an amide.

Carboxylic acid esters of formula I can be · a · conventional manner, e.g. · treatment with alkalis, especially by treatment with aqueous alcoholic sodium hydrox ^Du or sodium · potassium hydroxide, to hydrolyze at a temperature range between room temperature and the boiling temperature of the reaction mixture and either via a halide acids, or as described below, immediately announce.

The carboxylic acid esters of formula (I) can be converted directly into the corresponding amide by treatment with an alkyl-substituted lithium amide. The alkyl-substituted lithium amide is reacted preferably at room temperature with the corresponding ester.

The carboxylic acid or carboxylic acid ester of the formula I can be reduced in a manner known per se to the corresponding alcohol of the formula I. The reduction is preferably carried out using a metal hydride or an alkylated metal hydride in a solvent. Mixed metal hydrides, such as lithiumaluminium hydride or bis- [methoxyethyleneoxy] sodium aluminum hydride, are preferably used as hydrides. Suitable solvents include, but are not limited to, ethers, tetrahydrofuran or dioxane when lithium aluminum hydride is used, and ethers, hexane, benzene or toluene when diisobutylaluminum hydride or bis- [methoxymethyleneoxyoxy] sodium aluminum hydride is used.

The alcohol of the formula I can, for example in the presence of a base, preferably in the presence of sodium hydride, be etherified in an organic solvent such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide or else in the presence of an alkali metal alkoxide in alkanol. between 0 and room temperature, with an alkyl halide such as ethyl iodide.

The carboxylic acid of the formula I forms salts with bases, in particular with alkali metal hydroxides, preferably sodium hydroxide or potassium hydroxide.

The compounds of the formula I can be present as mixtures of cis / trans isomers, which can be optionally separated into cis and trans components in a manner known per se or can be isomerized to compounds with trans-con-regulation.

The compounds of formula I are pharmacodynamically valuable substances. They can be used for topical and systemic therapy of benign and malignant neoplasias, premalignant forests, as well as for systemic and local prophylaxis of said affections.

The compounds according to the invention are furthermore suitable for the topical and systemic therapy of acne, psoriasis and other dermatoses associated with pathological changes in skin cornea, as well as inflammatory and allergic dermatological affections. The compounds according to the invention of the formula I are furthermore also used for combating mucosal diseases with inflammatory or degenerative diseases. metaplastic changes.

The toxicity of the new class of compounds is negligible. For example, when 9- [2,6-dichloro-4-methoxy-5-methylphenyl) -3,7-dimethyl-nona-2,4,6,8-tetraenoic acid ethyl ester is administered intraperitoneally to mice of weight 30 · g at a daily dose of 6 mg / kg, these mice show no signs of hypervitaminosis A after 14 days [total of 10 application days].

Only at a daily dose of 12 · mg / kg, after 14 days [total of 10 application days], animals show the first signs of a weak byper, vitamosis A, which results in a weight loss of 20 ° / o, moderate hair loss and slight skin blunting .

The effect of the reaction products manifested in tumor suppression is pronounced. In the papiaoma assay, diminution of the tumors induced by dimethylphenzanene and crotone oil was observed. Diameter papilloma over two weeks diminished when applying ethyl traperhoneální ^ O ^ O ^ ďchlor -metboxy-5-methylphenyl) ^i3,7id, metbyliiona-2,4,6,8-tetrae.nové acid at 25 mg / kg 85%, 12 mg / kg / week · 59%, 6 m'g / kg / week 42%.

Oral application of 9- (2,6-chloro-4-oxy-5-ethylene-N, N-dimethylnona-2,4,6,8-tetraenoic acid ethyl ester) reduced the diameter of the induced tumors over two weeks [5 single doses / week] at 25 mg [5x5 mgl, / kg / week by 72%, at 12.5 mg [5x2.5 mg] / kg / week by 62%, at 6.25 mg [5x1.25 mg] / kg / week by 43%, at 3.0 mg [5x0.60 mg] / kg / week by · 41%.

The compounds of formula I can therefore be used as medicaments, for example in the form of pharmaceutical preparations.

Formulations which are systemically administrable may be prepared, for example, by adding the compound of formula I as an active ingredient to non-toxic, inert, solid or liquid carriers which are customary in such formulations.

The compositions may be administered enterally or parenterally. For enteral administration, for example, compositions in the form of tablets, capsules, dragees, hairs, suspensions, solutions and suppositories are suitable. For. parenteral administration are suitable formulations in the form of solutions for infusion or injection.

The dosage in which the compounds of the invention are administered may vary according to the type of administration and the mode of administration, as well as the requirements of the patients.

The compounds of the invention may be administered in an amount of from about 1 to about 30 mg per day in single or multiple doses. A preferred dosage form is a capsule containing from about 1 mg to about 10 mg of the active ingredient.

The preparations can contain inert or also ^{farmakodynam:} cally active ingredient. Tablets or granules may contain a variety of binders, fillers, carriers or diluents. Liquid preparations can be used, for example, in the form of sterile, water-miscible solutions. The capsules may contain, in addition to the active ingredient, a filler or thickener. In addition, flavor enhancers as well as substances usually used as preservatives, stabilizers, moisture-retaining agents and emulsifiers, as well as salts for varying the osmotic pressure, putters and other additives may be present in these formulations.

The above-mentioned carriers and diluents may consist of organic or inorganic substances, for example water, gelatin, lactose, starch, magnesium salt of stearic acid, talc, acacia, polyalkylene glycols and others. It is a prerequisite that all excipients used in the manufacture of these preparations are not toxic.

For topical application, the substances according to the invention are advantageously used in the form of ointments, elixirs, creams, solutions, lotions. lotions, creams, suspensions, and the like. Ointments and creams are preferred. These topical formulations can be prepared by mixing the compounds of the invention as active ingredients with non-toxic, inert, topical, suitable solid or liquid carriers which are customary in such formulations.

Suitable for topical use are suitably about 0.01 to about 0.3%, preferably 0.02 to 0.1% solution, as well as about 0.05 to about 5%, preferably about 0.05 to about 1% ointment or creams.

These preparations can optionally be admixed with antioxidants, for example tocopherol, N-methyl-γ-tocopheramine, as well as butylated hydroxyanisole or butylated hydroxytoluene.

Example 1

42 g of ethyl 7-formyl-3 are added to 100 g of 2b < 3 &gt; -n-methyl-5-methylbenzyltriphenylphosphonium chloride which was made from 52 g of 2,6-dichloro-4-methoxy-3-methylbenzyl chloride and 57 g of triphenylphosphine. -methyl-2,4-trienic acid and, after addition of 120 ml of 1,2-butylene oxide, the mixture is heated to 80-85 ° C with stirring for 4 hours. hexane (1: 1) and extracted thoroughly with a mixture of methanol and water (60:40), the solution is evaporated under reduced pressure, and the oily residue is purified by adsorption on silica gel (eluent: toluene). 6 didhlor 4lmethoxy-5-m.ethylfeny]) -3,7-dimethybnona-2,4,6,8-te ^l traenové acid, which was obtained from the eluate was recrystallized from ethyl · benzene and hexane (50 50 ° C to 100 ° C to 101 ° C.

The 2,6-dichlyr-4-methoxy-5-methylbeyzyltri [1,4-a] n-yl] -cyclohexanone chloride used as starting material can be prepared, for example, as follows:

103.0 g of 2-nitro-4,6-dichlorotoluene are dissolved in 500 ml of ethyl acetate. The solution is hydrogenated under normal conditions after addition of 20 ml of Raney Nickel. The hydrogenation is stopped when 43 liters of hydrogen are consumed. The catalyst was filtered off with a stream of carbon dioxide and the filtrate was washed with ethanol. The combined filtrates were evaporated under reduced pressure. The remaining 2-amino-4,6-di-chlorotoluene boils after rectification at 85 ° C 753.3 Pa.

2-Amino-4,6-dichlorotoluene (g) was gradually added to 250 ml of concentrated sulfuric acid with stirring and cooling. The temperature rises to +60 ° C. The mixture is cooled by slowly adding 750 g of ice to 0 ° C and then a solution of 26.4 g of sodium nitrite in 80 ml of water is added dropwise over 3 hours. The reaction mixture was further stirred at 0 to +10 ° C for 90 minutes and then filtered. The filtrate is added dropwise to steam distillation with the addition of 600 ml of sulfuric acid (50% by volume). The filtrate is extracted 3 times with 1000 ml of methylene chloride. The methylene chloride extract was dried over sodium sulfate and evaporated. The remaining 2-hydroxy-4,6-dichlorotoluene melts after recrystallization from hexane. at 51-52 ° C.

To 79 g of 2-hydroxy-4,6-dichlorotoluene, after addition of 400 ml of methanol and 85.5 ml of dimethyl sulfate, 256.5 ml of potassium hydroxide (25% w / v) were added dropwise with stirring. The reaction mixture, which was heated to reflux, was stirred at reflux for 4 hours and then evaporated. The residue is taken up in 600 ml of water. The aqueous solution was extracted with ether (3.times.600 ml). The ether extract was washed with water until neutral, dried over sodium sulfate and evaporated under reduced pressure. The remaining 2-methoxy-4,6-dihydrotoluene boils after rectification at 69-70 ° C.

68.0 g of 2-methoxy-4,6-dichlorotoluene are mixed with 235 ml of acetic acid, 446 ml of hydrochloric acid (37% w / v) and 107 ml of formaldehyde (35%) and the mixture is stirred for 3 hours at room temperature. at 70 ° C and, after cooling, · · poured into 2000 mL water. the aqueous solution was extracted 3 times with 1000 ml of methylene chloride. the extract was washed 3 times with 1000 ml of water, dried over sodium sulfate and evaporated. the residual ^2,6-dic: chloro The 4-methoxy-5-methylbenzyl chloride is purified by adsorption on silica gel (eluent: low-boiling petroleum ether) to give the title compound after recrystallization from hexane at 84-85 ^° C.

The 2,6-dichloro-4-methoxy-5-methylbenzyl chloride obtained is then reacted with triphenylphosphine as described in Example 1 to give 2,6-dichloro-4-methoxy-5-methylbenzyltriphenylphosphonium chloride.

Example 2

In an analogous operating procedure to that described in Example 1, the following can be produced:

2,6-diblim-4-methoxy-5-met ^; hylbenzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-trienic acid ethyl ester 9- (2,6-dibromo-4-methoxy-5'-methyl-phenyl) -3,7-dimethyl-on-2-ethyl ester, 4,6,8-tetraenoic acid, m.p. 101-102 ° C.

2,6-e-Dmrom-the; tho5y-5- _m ythylbenzyltrltenylf (slfonium.chlorid, which is used as, a starting material is available in an analogous manner to that described in Example 1, from 2-nitro-0,6- melting point 64-65 ° C, over 2-amino-0,6-di ^: bromemtoluene boiling point 85 ° c / 53.3 Pa, over 2-hydroxy-4,6-dl · bromteluene melting point 101-10 ' 2 ° C over ^2,6-diC hler-4-methexy-5-methylbenzyl.

Example 3

Dissolve 52 g of 1-ethyl-carbenyl-2,6-dimethyl-heptatyl, 3,5-triethyl-7-triphenylphosphoric bromide in 220 ml of dimethylformamide. After adding 21.9 g of 2,6-dichloro-4-methexy-5-methylbenzaldehyde, the solution is cooled to 10 ° C, a solution of 2.4 g of sodium in 60 ml of absolute ethanol is added dropwise, and the mixture is stirred for 12 hours. at room temperature. The reaction mixture was then diluted with toluene / hexane 1: 1 and extracted with a 60:40 mixture of methanol and water. The solution is then evaporated under reduced pressure. The remaining 9- (2,6-dichloro-O-methyl-5-methylphenyl-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid ethyl ester melts after adsorption on silica gel (eluent: toluene) and recrystallization from benzene / hexane (50:50) at 99-100 ° C.

2,6-Dichloro-4-methoxy-5-methylbenzaldehyde, m.p. 110 DEG-111 DEG C., which is used as starting material, can be prepared, for example, from 3,5-dichloro-2-methylphenel; 52 ° C, over 3,5-dichloro-2-methylthylanisole, boiling point 76 ° C / 40 · Pa, n _D ²⁴ = 1,538, over 2,6-dichloro-4-methexy-5-methylbenzyl chloride, melting point 85 to 86 ° C.

EXAMPLE 4 g of 5- (2,6-dichloro-4-methyl-5-methylphenyl) -ZH-pentaphtho [alpha] -4,4-diene-1-thienylphenylphenol bromide was added to 100 ml of dimethylformamide under a nitrogen atmosphere and added under nitrogen. Cooling at 5-10 ° C add 1.75 g of sodium hydride (50%) in mineral oil over 20 minutes. The mixture is stirred at a temperature of about 10 ^DEG C. for 1 hour, then 7.1 g of ethyl ester are added dropwise at a temperature of 5-8 DEG. Of 3-formylcrotenevic acid, heated at 65 ° C for 2 hours, then poured into ice water and extracted with sodium chloride (100 mL). The extract was washed with a 6: 4 mixture of methanol and water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 5- (2,6-dichloro-4-methoxy-5-methylphenyl) -3,7-dimethylnona-2,4,6,8-tetratenoic acid ethyl ester melts after recrystallization from benzene / hexane (50: 50) at 100 to 101 ° C.

5- (2,6-Dichloro-4-methexy-5-methylphenyl) pent-2,4-diene-tritenylphosphemum bromide, which is used as starting material, can be prepared, for example, from 3,5-diclhoeine. 2-methylphenyl, m.p. 51-52 ° C, via 3,5-dichloro-2-methylanisel, bp 76 ° C / 4 ^; 2 Pa, n _D 24 = 1.5538, via 3,5-dichloro-2-methyl-p-anisaldehyde, melting point 110-111 ° C, via 4- (2,6-dichloro-4-methety-5- Ethylphenyl) but-3-en-2-ene, m.p. 55-56 ° C, via 5- (2,6-dichloro-4-methyl-5-methylphenyl) -3-methyl-3-hydroxypenta-4-en-1 -in, np24 = 1.5718, via 5- (2,6-di-chloro-4-methyl-5-methylphenyl) -3-methylpenta-2,4-dien-le · l, no23 = 1,5661 .

EXAMPLE 5 g 9- (2,6-Dichloro-4-methyl-5-methylphenyl) -1,7-dimethyl-aona-2,4,6,8-tetraenoic acid ethyl ester is dissolved in 750 ml of ethanol. To the solution was added 41 g of potassium hydroxide in 63 ml of water. The mixture was heated to reflux for 30 minutes under nitrogen, then cooled, poured into water and acidified with hydrochloric acid. The precipitated 9- (2,6-di201509 chloro-4-ethoxy-54-methylphenyl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid melts at 252-254 ° C.

Example 6 g. 9- (2,6-Dimethyl-4-nitro-5-nitro) -3,7-dimethylnona-2,4,6,8-tetraenoic acid is dissolved in 750 g of tetrahydrofuran. To the solution is added 2.64 ml of phosphorus trichloride (0.7 mol), after 12 hours under reduced pressure at 30 ° C, the solution is concentrated to 1/2 of its original volume and at 0 to 5 ° C the reaction solution dropwise to a tetrahydrofuran solution containing 14.6 g of ethylamine. The reaction mixture was stirred at room temperature for 1 hour, then poured into saturated aqueous sodium chloride solution and extracted with methylene chloride. The extract was washed with brine, dried and evaporated under reduced pressure. The remaining 9- (2,6-dichloro-4-methoxy-5-methyl-ethyl-phenyl) -3,7-diethyl-nona-2,4,6,8-ethanoic acid ethylamide is purified by adsorption on silica gel (eluent: diethyl ether) and recrystallization from ethyl acetate melts at. 128 DEG-129 DEG.

Example 7

13.8 g of ethyl 9- ^{(2,6-dichloro-4-methoxy-5-methyl,} hylfeínyl) -3,7-dimethyl-non-2,4,6,8-tetraenoic acid was dissolved in the 170th ml of toluene. The solution was stirred and under an atmosphere. The mixture was cooled and treated with 80 ml at 0 to 2 ° C. 20% solution of di-isobutylaluminum hydride in toluene. The reaction mixture was stirred at 0 ° C for 30 minutes, then poured carefully into water and extracted. The toluene extract is washed several times with water, dried over sodium sulphate and evaporated under reduced pressure. The remaining 9- (2,6-dichloro-d-methoxy-D-imidomethyl) -3,7-dimethylnona-2,4-diothien-1-ol is purified by adsorption on silica gel (eluent: diethyl ether). ). The alcohol melts after recrystallization from benzene at 128-129 ° C.

Example 8

8.1 g of 9- (2,6-dichloro-4-methyloxy-5-methylphenyl) -3,7-dimethylnollat-2,4,6,8-tetraethylen-1-ol are dissolved in 10 ml of tetrahydrofuran. 10 ml of methyl iodide are added dropwise at 0 DEG to 2 DEG C. after the addition of 10 g of sodium hydride suspension in oil washed with benzene at 0 DEG. The reaction mixture is stirred at 0 ° C for 2 hours, then at room temperature for 12 hours, then diluted with 200 ml of toluene and carefully added to water. The toluene phase is separated, washed with water until neutral, dried over sodium sulfate and evaporated under reduced pressure. The remaining 9- (2 ', (4- (4-chloro-4-methoxy-5-methyl-4'-methyl) -phenyl) -3,7-dimethyl-nona-2,4,6,8-etraene-1-methyl ester) The resulting ether melts after recrystallization from hexane at 104-105 ° C.

Example 9 g of 9- (2,6-dichloro-4-methoxy-5-piperidin-3-yl) -3,7-dimethylamino-2,4,6,8-tetraenoic acid ethyl ester (mixture of cis / isomers) 50:50) was chromatographed on 1.5 kg of silica gel (stage Iictivity) using hexane / toluene (80:20) as eluent. 9- (2,6-dichloro-4-methoxy-5 t ^tmethyl! Phenylthio-3,7-dimethyl-non-2-cis-4T-8--transt6ttrans tгanstetraenové acids which can be isolated from the front fraction was recrystallized from hexane at 108-109 ° C.

Example 1 a d A

Manufacture of capsule filling compositions as follows:

9- (2,6-dichloro-4-methyl-5-methylphenyl) -3,7-dimethyl-nona-2,4,6,8-tetetiraene ethyl ester 1mg wax mixture 50.5mg vegetable oil 98.0mg trisodium salt of ethylenediamine tetraacetic acid 0.5mg single weight capsule 150 mg active ingredient content per capsule 1 mg

Example B

Manufacture of an ointment containing 0,1 ^Ό / ο of the active substance as follows:

9- (2,6-Dichloro-4-methoxy-5-methyl-phenyl) -3,7-dimethyl-naphth-2,4,6,8-ethyl ester

-tetraenoic acid 0.1 cetylalk-shave 2.7 sheep wool fat 6.0 vasellna 15.0 Distilled water to 100.0

Claims (5)

OBJECT OF THE INVENTION CLAIMS 1. A process for the production of substituted phenylnonatetraene compounds of the formula EMI2.0 in which they are R 1 and R 2 are chlorine or bromine; R 3 is hydroxymethyl, alkoxymethyl of 1 to 6 carbon atoms in the alkoxy group, carboxyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy group or mono- or di (lower) alkylcarbamoyl of 1 to 6 carbon atoms in the alkyl radicals, as well as and salts thereof, wherein a compound of formula (II) is treated with a compound of formula (III) wherein m = 0 and n = 1 or m = 1 and n = 0, one of A and V being a formyl group; and the other of these represents a triarylphosphonium methyl group of the formula —CH2 — Ρ [Χ] 3®ΥΘ, where X is an aryl group and Y anion of an organic or inorganic acid, R 1 and R 2 are as defined above and Rd in the case where V is a formyl group means an alkoxymethyl group having 1 to 6 carbon atoms in an alkoxy group, a carboxyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in an alkoxy group or a mono- or di (lower) alkylcarbamoyl group having 1 to 6 atoms and in the case where V represents a triarylphosphonium methyl group, Rd represents a carboxyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy group or a mono- or di (lower) alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl residues , in the presence of an acid binding agent or alkylene oxide at temperatures between room temperature and the boiling point of the reaction mixture, whereupon the acid thus obtained is optionally converted into a salt or the carboxylic acid of formula I is converted to a carboxylic acid ester of formula I or amide of formula I the carboxylic acid of formula I is converted to a carboxylic acid or an amide of formula I, or a carboxylic acid of formula I or a carboxylic ester of formula I is reduced to the corresponding alcohol of formula I and optionally etherified. 2. A process according to claim 1, wherein the phosphonium salt of formula II or III is treated with an aldehyde of formula III or II in the presence of an epoxide, in particular in the presence of ethylene oxide optionally substituted by a lower alkyl radical of 1 to 6 carbon atoms. 1,2-butylene oxide, optionally with the addition of a solvent. 3. A process according to claim 1 or 2, wherein the 2,6-dichloro-4-methoxy-5-methylbenzyltriphenylphosphonium halide is treated with an alkyl ester of 7-formyl-3-methyl-octa-2,4,6-trienic acid of 1 to 6 carbon atoms in alkyl. 4. The process of claim 1, wherein the carboxylic acid of formula I is converted to the acid halide of formula I and is treated with a mono- or di (lower) C1-C6 alkyl amine. 5. The process of claim 4, wherein 9- (2,6-dichloro-4-methoxy-5-methylphenyl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid is converted. to an acid halide treated with ethylamine to give 9- (2,6-dichloro-4-methoxy-5-methylphenyl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid ethylamide.