FI62280C - ANALOG FOUNDATION FOR FRAMSTAELLNING AV NYA TUMOERHAEMMANDE POLYENFOERENINGAR - Google Patents

Description

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Patent- och registerstyrelsen 'Antökan utlajd oeh utl. * Krlft * n pubUcerad 31.0o.02 (32) (33) (31) PyrdsKy «toikuui - B« «and prior 30.03-73 Switzerland-Switzerland (CH) U603 / 73 ( 71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel, Switzerland-Switzerland (CH) (72) Werner Rollag, Basel, Rudolf Ruegg, Bottmingen, Gottlieb Ryser, Basel, Switzerland (di) (7I *) Oy Kolster Ab (5 * 0 Analog method for the preparation of new antitumor polyene compounds - Analog for the production of new anti-tumor polyene compounds

The invention relates to an analogous process for the preparation of novel antitumor polyene compounds of the formula H 1

Klt ['R 1 R 5 wherein R 1 and R 2 represent lower alkyl; R 1 is hydrogen, lower alkyl, halogen, nitro, amino, mono- or di-previous alkylamino; R 1 is hydrogen, lower alkyl, lower alkoxy or previous alkeneoxy; R 2 is hydrogen or lower alkyl, provided that at least one of the radicals R 2 -R 2 ° C is lower alkyl, both of which do not simultaneously mean hydrogen, and when R 3 is halogen , R 1 is not alkoxy; and R 9 is hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxycarbonyl, alkeneoxycarbonyl, alkyloxycarbonyl, carbamoyl, mono- or di-lower alkylcarbamoyl, morpholinocarbonyl or 3-pyridylmethyleneoxycarbonyl, and

In J. Chem. Soc. 1953, 1571-1577 and 1958, 1855-1861 describe growth-promoting retinoids having a phenyl group methylated at either the 3- or 1 + position. In contrast to the known retinoids, the retinoids of the formula I according to the invention have either a total of two or three substituents in the 3-, U- and 5-positions or no lower alkyl radicals. In addition, the retinoids of formula I have antitumor properties and the new compounds are by far superior to known compounds having a close structure and a similar effect. This is evident from the following comparative experiments. Due to their very good therapeutic properties, compounds of the formula I in which R 1, R 4 and R 2 represent methyl, R 4 is methoxy, R 4 is hydrogen and R 8 is carboxy, ethoxycarbonyl or ethylcarbamoyl are preferred.

In particular, the above-mentioned lower alkyl and alkenyl groups contain up to 6 carbon atoms, such as a methyl, ethyl, propyl, isopropyl or 2-methylpropyl group and a vinyl, allyl or butenyl group. Lower alkoxy and lower alkenoxy groups likewise contain in particular up to 6 carbon atoms, such as a methoxy, ethoxy or isopropoxy group and a vinyloxy or allyloxy group.

Of the halogen atoms, fluorine or chlorine are preferred.

The amino group may be mono- or di-substituted with branched or branched lower alkyl, e.g. methyl, ethyl, isopropyl.

Said alkoxymethyl and alkoxycarbonyl groups contain in particular alkoxy radicals having up to 6 carbon atoms. These may be branched or unbranched, such as a methoxy, ethoxy or isopropoxy residue.

But in addition to this, higher alkoxy radicals having 7 to 20 carbon atoms are also possible, of which in particular a cetyloxy radical. Said alkoxy radicals may be substituted by functional groups, e.g. nitrogen-containing groups, such as, for example, an optionally alkyl-substituted amino or morpholino group, or by a piperidyl or pyridyl radical. The alkeneoxy and alkyloxycarbonyl groups also contain in particular 6-alkoxy radicals and alkyne. a carbon atom such as an allyloxy or propargyloxy residue.

Alkanoyloxymethyl groups are due in particular to lower alkanecarboxylic acids having 3 to 6 carbon atoms, e.g. acetic, propionic or pivalic acid, but possibly also to higher alkanecarboxylic acids having J-20 carbon atoms, e.g. palmitic or stearic acid.

The carbamoyl group may be mono- or di-substituted with straight-chain or branched lower alkyl radicals, e.g. methyl, ethyl or isopropyl, such as, for example, a methylcarbamoyl, dimethylcarbamoyl or diethylcarbamoyl group.

The new compounds can be prepared in a manner known per se as follows: either a) a phosphonium salt of the formula Γ1 © Θ

R P W 3 Y

(IIa) -R 1 R 5 or a phosphonate of the formula ® R P - [*] IL J 2 r 3_ <IIb »ali-XyJ-B1 H5 is reacted with an aldehyde of the formula H_ ^ As ^ xA ^ rfi 7 (IIIl0 o or b) an aldehyde of formula 11 62280

O

ΐ2 1

R Jm H

R. I_R (Ile)

RiT ~ R1 R5 is reacted with a phosphonium salt of the formula,.

3 Y

or with a phosphanate of the formula, I One) z p 2i 0 or e) a sulfone of the formula

S0 "E

I2 (lid) R5 is reacted with compounds of formula 5 62280 I (ma)

B

or d) reacting a compound of formula% 1 1 'J (IIe) R m r -R 1 R 5 with a sulfone of formula (s) wherein m and n represent an integer 0 or 1 and n + m = 1; X is aryl and Y is an anion of an organic or inorganic acid; Z is alkoxy; E is an aryl or aralalkenyl radical which may be substituted by one or more electron-repellent or weakly electron-withdrawing groups; B is halogen, alkylsulfonyloxy or arylsulfonyloxy; R 1, R 2, R 3, R 2 and R 2 are as defined above; R 1 is carbonyl, alkoxycarbonyl, alkeneoxycarbonyl, alkyloxycarbonyl, di-lower alkylcarbamoyl or morpholinocarbonyl or 3-pyridylmethylcarbonyl and R 1 is a radical R and that the acid or amine obtained is, if desired, converted into a salt, or the carboxylic acid of formula I is converted into carboxylic acid esters of formula I or an amide of formula I, s 62280 or a Kaxbc 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 etherified.

In the triarylphosphonium group of the formula -P / x7_® ^ X, the aryl groups described in general comprise all known aryl radicals, but in particular mononuclear radicals, such as phenyl or lower alkoxy-substituted phenyl, such as tolyl, xylyl, mesityl, mesityl, mesityl, mesityl, mesityl . Of the inorganic acid anions, chlorine, bromine and iodine ions or hydrosulfate ions are preferred, and of the organic acid anions, tosyloxy ions are preferred.

In the dialkoxyphosphinyl group of the formula -P / z /, the alkoxy-1 * -O radicals described by Z are mainly lower alkoxy radicals having 1 to 6 carbon atoms, in particular methoxy or ethoxy.

Examples of aryl or aralkenyl radicals in the sulfone group of the formula SO 2 E, optionally substituted with one or more electrons, which are optionally substituted by one or more electrons, are: phenyl and styryl, both residues optionally substituted in the o-, m- or p-position , phenoxy, acetoxy; - dimethylamino, phenylmethylamino, acetylamino; - thiomethyl, thiophenyl, thioacetyl; - chlorine, bromine; - cyanilla; or - nitro at the m-position.

The starting materials of the formulas II and III are in part new compounds.

They can be obtained as follows:

Compounds of general formula Ha or Hb in which m = 0 and which contain a triarylphosphonium group fj-Ίζζ} or a dialkoxyphosphinyl group / ΪΓίι7 can be obtained, e.g., by treating the corresponding R 1 -R 1 -substituted benzene in the presence of a hydrohalic acid, e.g. optionally in a solvent, especially glacial acetic acid with formaldehyde and the resulting R 1 -R 4 -substituted benzyl halide / halide of formula Ile, where m = 0 / is reacted in a manner known per se with triarylphosphine in a solvent, preferably triphenylphosphine 62 or toluene or with a trialkyl phosphite, especially triethyl phosphite.

In the above, with the residues R.j-Rj. an alkoxy group in substituted benzene, can be attached, e.g., by alkylation to an existing hydroxy group. For example, the corresponding phenol is preferably reacted with an alkyl halide, e.g. methyl iodide or dimethyl sulphate, in a solvent, e.g. alcohol and in the presence of a base such as potassium carbonate.

Compounds of the general formula Ha or Hb in which m = 1 and which contain a triarylphosphonium group / IIIa or a dialkoxyphosphinyl group [iTbJ] can be obtained, for example, as follows: carried out on the corresponding, with radicals R1-R4. for substituted benzene, first a formylation reaction such that, e.g., the formylating agent is allowed to act on the starting compound. This can be done, for example, by formylating the starting compound in the presence of Levis acid. Suitable formylating agents are, in particular, the following substances: orthomuric acid ester, formyl chloride and dimethylformamide. Of the Levis acids, halides of zinc, aluminum, titanium, tin and iron, such as zinc chloride, aluminum trichloride, titanium tetrachloride, tin tetrachloride and iron trichloride, as well as halides of inorganic and organic acids, such as phosphorus oxychloride and methane, are particularly suitable.

The formylation can be performed if an excess of formylating agent is present, optionally without the addition of another solvent. However, it is generally recommended that the reaction be performed in an inert solvent, e.g. nitrobenzene, or in a chlorinated hydrocarbon such as methylene chloride. The reaction temperature may be between 0 ° C and the boiling point of the reaction mixture.

The resulting R 1 -R 4 -substituted benzaldehyde can finally be extended in a manner known per se by condensation with acetone in the cold, i.e. at a temperature in the range of about 0-30 ° C in the presence of an alkali, e.g. dilute aqueous sodium hydroxide, with residues R 1 -R 2. substituted phenyl-but-3-en-2-one, which can be converted in a manner known per se by an organometallic reaction, e.g. by a Grignard reaction by adding acetylene corresponding to the radicals R 1 -R 2 substituted by 3-methyl-3-hydroxy-Penta -U-eni-1-one. The tertiary acetylene carbinol obtained is finally partially hydrogenated in a manner known per se by means of a partially poisoned precious metal catalyst (Lindlay catalyst). The tertiary ethylene carbinol formed can finally be converted, under allyl treatment, by treatment with triarylphosphine, in particular triphenylphosphine, in the presence of a mineral acid, e.g. , the tertiary tfr 8 62280 ethylene carbinol can be converted to the corresponding halide of formula Ile where m = 1 after halogenation with a trialkyl phosphite, e.g. triethyl phosphite, to the corresponding phosphonate of formula Hb.

Sulfones of the formula IId in which m = 0 can be prepared, for example, by dissolving with the radicals R 1 -R 1. substituted phenol or the like halobenzene in a polar solvent, e.g. an alcohol such as methanol, ethanol or isopropanol or tetrahydrofuran or dimethylformamide, or also glacial acetic acid and reacted at room temperature with one or more electron withdrawing or electron withdrawing compounds of formula ® SE. a group-substituted aryl or aralkenyl residue, with the corresponding sulfinic acid, or with an alkali salt of this sulfinic acid. The sulfone can be isolated from the reaction mixture, e.g., by neutralizing the reaction solution by adding aqueous sodium hydrogencarbonate solution, and the sulfone is extracted as an organic solvent, e.g., ethyl acetate or ether.

Sulfones of formula IId where m = 1 can be obtained in a similar manner by reacting R 1 -R 2 -substituted phenyl-3-methyl-Penta-2,1 *-dien-1-ol or a halide of this alcohol with the sulfinic acid or this acid described above. with an alkali metal salt.

The compounds of formula IIIa-IIIe are also partly new:

Compounds of formula IIIb or IIIc in which n = 0 and which contain a triarylphosphonium group fl1TbJ or a dialkoxyphosphinyl group -phosphine in toluene or benzene, or with a trialkyl phosphite, especially triethyl phosphite.

Compounds of formula IIIb or IIIc in which n = 1 and which contain a triarylphosphonium group (IIIb7 or a dialkoxyphosphinyl group / ΪΙΙς, 7) can be prepared, for example, by reducing the formyl group of an aldehyde of formula IIIa where n = 1 with a metal hydride, e.g. sodium borohydride in an alcohol, e.g. ethanol or isopropanol, to a hydroxymethyl group. The resulting alcohol can be halogenated with a conventional halogenating agent, e.g. phosphorus oxychloride, and the resulting 8-halo-3,7 "dimethyl-octa-2,6-triene-1-carboxylic acid, a halide of formula IIId with n = 1, or an acid thereof the derivative is reacted with triarylphosphine in a solvent, preferably triphenylphosphine in toluene or benzene, or with a trialkylphosphite, especially diethylphosphite, to give the desired phosphonium salt of formula IIIb or 9,62280 to a phosphonate of formula IIIc.

Sulfones of formula IIIe where n = 0 can be prepared, e.g., by reacting 1 * -hydroxy-3-methyl-but-2-en-1-ol or an acetate or bromide of this alcohol in a polar solvent, e.g. in propanol or n-butanol as described above with the above-mentioned sulfinic acid or an alkali metal salt of this acid.

Sulfones of formula IIIe where n = 1 can be prepared in a similar manner as described above, e.g. by administering 8-hydroxy-3,7-dimethyl-octa-2,6, tri-triene-1-acid or an acetate or bromide of this alcohol. react with the above-mentioned sulfinic acid,

According to Wittig, the components are reacted in the presence of an acid scavenger, e.g. in the presence of an alkali metal alcoholate such as sodium methylate, or optionally alkyl substituted alkylene oxide, especially in the presence of ethylene oxide or 1,2-butylene oxide, optionally in a solvent such as chlorine. , or also in dimethylformamide, at a temperature between room temperature and the boiling point of the reaction mixture.

According to Horner's procedure, the components are condensed with a base and preferably in the presence of an inert organic solvent, e.g. sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or also with an alkali metal alcoholate in an alcohol, e.g. sodium methylate. in methanol at a temperature between 0 ° and the boiling point of the reaction mixture.

According to Julian's method of operation, the components are connected to one another by means of a condensing agent, expediently in the presence of a polar solvent. Suitable solvents are, for example, dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran and hexamethylphosphoric triamide, and further alcohols, such as methanol, isopropanol or tert-butanol. Suitable condensing agents which may be mentioned are, for example, strong bases: alkali and alkaline earth carbonates, in particular sodium carbonate; alkali metal hydroxides such as potassium or sodium hydroxide; alkali and alkaline earth alcoholates such as sodium methylate and especially potassium tert-butylate; alkali metal hydrides such as sodium hydride; alkylmagnesium halides such as methylmagnesium bromide; as well as further alkali metal amides such as sodium amide. The coupling is preferably carried out at lower temperatures, in particular at a temperature below the freezing point, e.g. in the temperature range between -50 ° and -80 ° C,

In certain cases, it has proved expedient to combine the above reactions in situ, i.e. the condensation components, without isolating the phosphonium salt, phosphonate or sulfone in question.

The carboxylic acid of the formula I can be converted in a manner known per se, e.g. by treatment with thionyl chloride, preferably pyridine, into an acid chloride which can be converted by reaction with an alcohol into an ester, with ammonia into an amide,

The carboxylic acid ester of the formula I can be hydrolysed in a manner known per se, e.g. by treatment with alkalis, in particular by treatment with aqueous alcoholic sodium or potassium hydroxide at a temperature between room temperature and the boiling point of the reaction mixture and amidated either via an acid halide or immediately described above.

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

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 with a metal hydride or an alkyl metal hydride in an inert solvent. Suitable hydrides are, in particular, mixed metal hydrides, such as lithium aluminum hydride or bis / methoxyethyleneoxy-7-sodium aluminum hydride. Suitable solvents are e.g. ether, tetrahydrofuran or dioxane if lithium aluminum hydride is used, and ether, hexane, benzene or toluene if diisobutylaluminum hydride or bis- / methoxyethyleneoxy-7-sodium aluminum hydride is used.

The alcohol of formula I can be etherified, e.g. in the presence of a base, preferably sodium hydride, in an organic solvent such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide, or also in the presence of an alkali metal alcoholate in an alcohol at a temperature between 0 ° C and room temperature. temperature, with an alkyl halide, e.g. ethyl 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, e.g. pyridine or triethylamine, at a temperature between room temperature and the boiling point of the reaction mixture.

The alcohol ester of the formula I can be oxidized in a manner known per se to the corresponding acid of the formula I. The oxidation is preferably carried out with silver (I) oxide and alkali in water or a water-miscible organic solvent at a temperature between room temperature and the boiling point of the reaction mixture.

The amine of the formula I forms addition salts with inorganic or organic acids. Examples which may be mentioned are: salts with hydrohalic acids, in particular hydrochloric or chromic acid, salts with mineral acids, e.g. sulfuric acid, or also salts with organic acids, e.g. benzoic acid, acetic acid, citric acid or lactic acid.

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

The compounds of formula I may be cis / trans mixtures.

The products of formula I are pharmacodynamically valuable compounds. They can be used for the local and systematic treatment of pre-malignant lesions of benign and malignant neoplasms, as well as for the systematic and local prophylaxis of said disease states.

They are still suitable for the local and systemic treatment of acne, dandruff and other skin diseases with severe or pathologically altered cornea, as well as inflammatory and allergic dermatological diseases. The process products of the formula I can further be used for the control of mucosal diseases in which inflammatory or degenerative or metaplastic changes occur.

The toxicity of the new class of compounds is low. 9- (i * methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraene-1-acid [7] and 9- (N-methoxy-2, For example, the acute toxicity of 3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1 *, 6,8-tetraene-1-acid ethyl ester / B7 is - as shown by the late toxicity after 20 days described in the table below - in mice. after intraperitoneal administration of the substance in beet oil at 700-1000 mg / kg.

12 62280

Acute toxicity DL mg / kg DL mg / kg DL n mg / kg

Substance A

After 1 day 1 * 000 1 * 000 1 * 000 After 10 days 5Ö0 700 890 After 20 days 580 700 890

Acute toxicity DL10 mg / kg DL ^ mg / kg DL ^ Q mg / kg

Subject B

After 1 day 1 * 000 1 * 000 1 * 000 After 10 days lUOO 1900 2600

After 20 days 710 1000 lUOO

The antitumor effect of the method products is significant. In the papilloma experiment, tumors induced with dimethylbenzanthracene and croton oil recover. Papilloma diameter decreases within 2 weeks when administered intraperitoneally

Substance A: at 50 mg / kg / week, at 38 J at 150 mg / kg / week at 69%

Substance B: at 25 mg / kg / week at 1 * 5 # 50 mg / kg / week at 63 #.

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

Formulations for systemic use may be prepared, for example, by the addition of a compound of formula I as active ingredient to non-rayon, inert, solid or liquid carriers conventional in such preparations.

The agents can be administered enterally or parenterally. Suitable for enteral administration are, for example, substances in the form of tablets, capsules, granules, syrups, suspensions, solutions and suppositories. Substances suitable for parenteral administration in the form of solutions for infusion or injection.

The dosages in which the method products are administered can always vary according to the mode of use and the quality of use, as well as according to the needs of the patient.

The process products can be administered in an amount of 5-200 mg daily in one or more doses. The preferred form of administration is capsules in a concentration of about 10 mg to about 100 mg of active ingredient.

The preparations may contain inert or also pharmacodynamically active additives. For example, tablets or granules may contain a variety of binders, excipients, carriers or diluents. Liquid preparations may be in the form of, for example, a sterile water-miscible solution. The capsules may contain, in addition to the active ingredient, an excipient or a thickening agent. Flavor enhancing additives may also be present, as well as substances conventionally used as preservatives, staching, wetting or foaming agents, further salts to change the osmotic pressure, buffers and other additives.

The above-mentioned carriers and diluents may consist of organic or inorganic substances, e.g., water, gelatin, milk sugar, starch, magnesium stearate, talc, acacia, polyalkylene glycol and the like. It is a prerequisite that all excipients used in the preparation of the preparations are non-toxic.

For topical use, the method products are suitably used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams and solutions are preferred. These topical preparations can be prepared by mixing the process products as active ingredient with non-toxic, inert, topical solid or liquid carriers which are customary in such preparations.

Suitable solutions for topical use are from about 0.01 to about 0.3%, preferably from 0.02 to 0.1%, and from about 0.05 to about 5%, preferably from about 0.1 to about 2, 0% ointments or creams.

The preparations may optionally be mixed with an antioxidant, e.g. tocopherol, N-methyl-γ-tocopheramine and butylated hydroxyanol or butylated hydroxytoluene.

comparison Tests

Effect of the compounds of the invention on the development of skin papilloma compared to retinoic anhydride derivatives.

Experimental Procedure

Groups of four mice were treated with test compounds and the diameter of the papilloma of each mouse was determined and the sum of the diameters was calculated and the diameters of each group were averaged. The measurement was performed before starting medication (day zero) and 2 weeks after the first medication (day 1U).

The increase or decrease in mean papilloma diameter was calculated as a percentage of the 0-day value.

The results are shown in Table I, which shows the parameters for your hypervitarainosis. . ,, _ _ papilloma regression; ED 50 ^ / week A and the therapeutic ratio T.R. = f- * τ. : -—: -: - τ ~ ^ ~ · - ~ hypervitaminosis A; mm. the dose / day is given in Bollag, Europ. J. Cancer, vol. 10 (197 * 0, pp. 732-733-

The lower the T.R. the better is the relationship between the antitumor activity and toxicity of the test compound.

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Example 1 228 g of 5- (1+ -nethoxy-2,3,6-trimethyl-phenyl) -3-methyl-Penta-2,1 +-diene-1-triphenylphosphonium bromide are added under nitrogen gasification to 910 ml of dimethylformamide and, with cooling, At 5-10 ° C for 20 min, containing 17.5 g of a suspension of sodium hydride (from about 50 ° C) in mineral oil. The mixture is stirred for 1 hour at about 10 ° C, then added dropwise at 5-8 ° C. 6.1 g of 3-formyl-crotonic acid butyl ester are heated for 2 hours at 65 [deg.] C., finally added to 8 liters of ice water and, after adding 300 g of sodium chloride, extracted thoroughly with a total of 18 liters of hexane. The extract is washed 5 times with 1 liter of methanol / water (6: 1+) and 2 times with 1.5 liters of water each time, dried over sodium sulfate and evaporated under reduced pressure. The remaining 9- (1 + -methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraene-1-acid-butyl ester, m.p. 80-81 °, can be converted to the free acid as follows: 125.8 g of 9- (U-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1 +, 6,8- tetraene-1-acid butyl ester is added to 2000 ml of abs. ethanol and a solution of 125.8 g of potassium hydroxide in 195 ml of water is added. The mixture is heated under nitrogen for 30 minutes, boiled for time, then cooled, added to 10 liters of ice water and, after adding about 2 l + 0 ml of conc. Hydrochloric acid / pH 2-1 + .7, extracted thoroughly with a total of 9 liters of methylene chloride. The extract is washed with about 6 liters of water neutrally, dried over calcium chloride and evaporated under reduced pressure. The residue is dissolved in 700 ml of hexane. The precipitated 9- (1 + -methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraen-1-acid melts at 228-230 ° C.

The starting compound 5- (1 + -methoxy-2,3,6-trimethyl-phenyl) -3-methyl-Penta-2,1 +-diene-1-triphenylphosphonium bromide can be prepared e.g. as follows: 500 g 2,3,5 -trimethylphenol is added to 181 + 0 ml of ethanol and 18U ml of water and 21 + 0 g of potassium hydroxide are added with gentle stirring. To the resulting clear solution is added dropwise at 0-5 ° C 30-1 + 5 min, within 626 g of methyl iodide. The reaction mixture is stirred for 2 hours at room temperature, finally refluxed for 12 hours at 60 ° C, then 5 liters of water are added. and extracted thoroughly with a total of 6 liters of ether. The extract is washed first with 3 liters of 3N sodium hydroxide solution, then twice with 1 liter of water each time, dried over sodium sulfate and evaporated under reduced pressure. The residual 2,3,5-trimethylanisole boils after purification at 88-90 ° C / 10 torr.

To 87.1 g of dimethylformamide is added dropwise with stirring at 10-20 ° C for 20-30 minutes. contains 181+ g of phosphorus oxychloride. The temperature is to be raised to 25 ° C towards the end of the addition. To the resulting mixture is added under cooling for 20 min. at 10-20 ° C 150 g of 2,3,5-trimethylanisole. The reaction mixture is slowly heated to a maximum of 115 ° C, stirred for 6 hours at 100 ° C to complete the reaction, poured into 2 kg of ice / water 1: 1 after cooling and after adding 500 ml of benzene 500 g of sodium acetate are added. The resulting aqueous phase is separated after stirring for 1 hour and re-extracted with 1000 ml of benzene. The combined benzene extracts are washed successively with 1 + 80 ml of 1.5N hydrochloric acid and 500 ml of water, dried over sodium sulphate and filtered through 20 g of decolorizing carbon. The filtrate is evaporated under reduced pressure. The remaining 2,3,6-trimethyl-p-anisaledhyde melts after recrystallization from hexane at 65-66 ° C.

260 g of 2,3,6-trimethyl-p-anisaldehyde are added to a mixture of 3500 ml of acetone and 11 + 00 ml of water and added at 0-5 ° C for about 30 minutes. within stirring 730 ml of 10% by weight sodium hydroxide solution. The mixture is stirred for 3 days at room temperature and finally, after the pH has lowered by adding acetic acid to U ~ 5, it is concentrated under reduced pressure. The concentrate is extracted with a total of 3000 ml of ether. The ether extract is washed first with 700 ml of 5% aqueous sodium bicarbonate solution, then with 700 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residual oily 1- + (1 + -methoxy-2,3,6-trimethyl-phenyl) -but-3-en-2-one boils after purification at 120-127 ° C / 0.05 torr.

36.1 + 5 g of magnesium are etched with a small amount of iodine, added to 1000 ml of tetrahydrofuran and, under a nitrogen atmosphere, added for 1 + 5 min. containing 162.5 g of ethyl bromide dropwise. The temperature is then initially intended to be 8-10 ° C. It may rise to 25 ° C towards the end of the addition. The reaction mixture is stirred, optionally with a further addition of 5 ~ 10 ml of alkyl bromide, until the magnesium is completely dissolved. The resulting Grignard solution is finally added dropwise at 0 ° C to a saturated solution of acetylene-tetrahydrofuran prepared from 650 ml of tetrahydrofuran by gasification for 3 hours with acetylene at -10 to -5 ° C. The reagent is stirred for 1 hour at 0 ° C, then 30-1 + 5 min is added. a solution of 218 g of 1 + - (1 + -methoxy-2,3,6-trimethyl-phenyl) -but-3-en-2-one in 250 ml of tetrahydrofuran is added dropwise by acetylene gasification at 0 ° C. The reaction mixture is stirred for 2 hours at 0 [deg.] C. and finally for 12 hours at room temperature, then 1: 1.5 kg of ice-water is added 3.5: 1, 700 ml of 3N hydrochloric acid are added to bring the pH to about 1 + and thoroughly extracted with a total of 3 liters of ether. The ether extract is washed with a total of 2 liters of water neutrally, dried over sodium sulfate and filtered through 20 g of decolorizing carbon. The filtrate is evaporated under reduced pressure, the remaining 5- (4-methoxy-2,3,6-trimethyl-phenyl) -3-methyl-3-hydroxy-penta-1-en-1-yne melts after purification at 125-135 ° C / 0.0U torr at 58-60 ° C.

2 hk g of 5- (4-methoxy-2,3,6-trimethyl-phenyl) -3-methyl-3-hydroxy-pentan-1-en-1-yne are dissolved in 1 + 00 ml of hexane and after the addition of 1 + 5 g of partially poisoned palladium catalyst are hydrogenated at room temperature under normal pressure. The hydrogenation is stopped for about 1 + 0-60 min. after taking up the amount of hydrogen required to saturate the acetylene-ethylene bond £ 25 liters_7- The hydrogenation solution is filtered. The filtrate is washed with 300 ml of ethyl acetate-acetic acid 62280 23 and evaporated under reduced pressure. The remaining 5- (N-methoxy-2,3,6-trimethyl-phenyl) -3-methyl-3-hydroxy-pent-1,1-diene melts at 1 * 6-U7 ° C.

2 g of 5- (U-methoxy-2,3,6-trimethyl-phenyl) -3-methyl-3-hydroxy-Penta-1,1-diene are dissolved in 2,00 ml of benzene. To the solution is added 3 * 3 g of triphenylphosphine hydrobromide, stirred for 2 hours at 60 ° C, then cooled and separated from benzene. The base layer is digested 1+ times with 500 ml of benzene each time and, after separating the wash benzene, it is dissolved in 700 ml of methylene chloride. The solution is evaporated under reduced pressure. The remaining 5- (U-methoxy-2,3,6-trimethyl-phenyl) -3-methyl-Penta-2,2-diene-1-triphenylphosphonium bromide is dried before further treatment in vacuo.

The 2-fornyl-crotonic acid butyl ester used as a condensation component can be prepared, for example, as follows: 1775 g of lead tetraacetate (from $ 90) are gradually added over 30 minutes. at 25-300 ° C to a solution of 1000 g of L (+) tartaric acid dibutyl ester in 3750 ml of benzene. The reaction mixture is finally stirred for 1 hour at room temperature. The bottom layer is filtered and extracted with 500 ml of benzene. The benzene extract is evaporated under reduced pressure. After purification, the remaining glyoxalic acid butyl ester boils at 50-65 ° C / 12 torr.

836 g of the glyoxalic acid butyl ester obtained are added to 376 g of propionaldehyde. U0.8 g of di-n-butylamine are added dropwise to the mixture at 60 ° C. The reaction temperature is not intended to rise above 106 ° C. The reaction mixture is then stirred for 2 hours at 106-111 ° C, cooled and dissolved in ether. The ether extract is washed successively with 500 ml of 1N sulfuric acid, 700 ml of water, 1000 ml of 5 # aqueous sodium bicarbonate solution and finally 1000 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residual 3-formyl-crotonic acid butyl ester boils after purification at 93 ° C to 105 ° C / l torr.

Example 2

According to the procedure described in Example 1, the following can be prepared: - from 5 - ((4-allyloxy-2,3,6-trimethyl-phenyl) -3-methyl-penta-2,1-diene-1-triphenylphosphonium bromide by condensation with 3-formylcrotonic acid ethyl ester; 9- (U-Allyloxy-2,3,6-trimethyl-phenyl) -3,7'-dimethyl-nona-2,1 +, 6,8-tetraene-1-acid ethyl ester and from the resulting ester - 9- (1 * (8'-yloxy-2,3,6-trimethyl-phenyl) -3,5-dimethyl-nona-2,1 +, 6,8-2,1 +, 6,8-tetraene-1-acid, m.p .: 198 -200 ° C.

2h 62280 The starting 5- (4-allyloxy-2,3, β-trimethyl-phenyl) -3-methyl-Penta-2,2-diene-1-triphenylphosphonium bromide can be prepared as described in Example 1 by alkylation 1, 3,5-Trimethylphenol to allyl bramide 11a to 1,3,5-trimethylphenyl allyl ether / b.p. 76-80 ° C / 0.05 torr, formylated ether to k-allyloxy-2,3,6-trimethylbenzaldehyde / b.p. 90-102 ° C (0.15 Torr), condensation of the aldehyde obtained with acetone to give k- (U-allyloxy-2,3,6-trimethyl-phenyl) -but-3-en-1-allyl (b.p. . 135-138 ° C / 0.005 torr, reacting the resulting ketone with acetylene to give 5- (allyloxy-2,3,6-trimethylphenyl) -3-methyl-3-hydroxy-penta-4-en-1-yne, by hydrogenation partially obtained tertiary acetylene carbinol 5- (k-allyloxy-2,3,6-trimethylphenyl) -3-methyl-3-hydroxy-pent-1, +) diene and reacting the resulting tertiary ethylene carbinol with triphenylphosphine with hydrobromide. The obtained 5 '(N-allyloxy-2,3,6-trimethyl-phenyl) -3-methyl-Penta-2,6-diene-triphenylphosphonium bromide melts at -116 ° C.

Example 3 28.5 g of 5 '- (4-methoxy-2,3,6-trimethyl-phenyl) -3-methyl-penta-2,1 +-diene-1-triphenylphosphonium bromide are added under nitrogen gasification to 2 .mu.l of isopropyl alcohol. . The mixture is cooled after the addition of 0.12 g of BHT to -35 ° C and at this temperature is added with vigorous stirring for 5 min. containing 7.50 g of 3-formylchrotyl acetate. Finally, 7.2 g of 50% by weight of potassium hydroxide solution are stirred into the reaction mixture - the temperature should not rise above -25 ° C - after stirring for 1 hour at -30 ° C, 90 g of water are added to the mixture with 100 g of water. ice and 90 ml of hexane. The hexane layer is separated. The aqueous phase is shaken 5 times with 90 ml of hexane each time. The combined hexane extracts are shaken 5 times with 180 ml of methanol / water 80:20 each time. The hexane phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 1-acetoxy-9- (N-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,2,6,6-tetraene oil can be purified by adsorption on Kiesel gel / eluent: hexane / ether 80:20.

Example 5+

According to the procedure described in Example k, the following can be prepared: - from pentamethyl-benzyl-triphenylphosphonium chloride by condensation with 7-formyl-3-methyl-octa-2,1 +, 6-triene-1-acid-butyl ester 9- (pentamethyl-phenyl) -3,7 " dimethyl-nona-2,1,6,8-tetraene-1-acid-butyl ester / oil and from the resulting ester - 9- (pentamethyl-phenyl) -3,7-dimethyl-nona-2,11,6; 8-tetraene-1-acid,

Jp. 228-229 ° C.

25 6 22 8 0 The pentamethylbenzyl triphenylphosphonium chloride used as starting material can be prepared, for example, as follows: 18.5 g of pentamethylbenzene, 193 ml of glacial acetic acid, 355 nil of concentrated hydrochloric acid and UU g of formaldehyde (35%) are heated to 65 ° C. The reaction mixture is stirred at this temperature for 3 hours, then after re-addition of 18.1 g of formaldehyde (35 l) is stirred for a further 3 hours, then cooled to room temperature and extracted thoroughly with benzene for a further 12 hours. The benzene extract is washed successively with water, dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated under reduced pressure. The remaining pentamethylbenzyl chloride melts after recrystallization from hexane at 80-81 ° C.

101.6 g of pentamethylbenzyl chloride, 1.9 g of triphenylphosphine and 250 ml of toluene are stirred for 5 hours at 100 ° C. Upon cooling the reaction mixture, the precipitated pentamethylbenzyl triphenylphosphonium chloride melts after slurrying and washing with low boiling petroleum ether at 258-259 ° C.

Example 5 16 g of 3-chloro-2,1 ', 6-trimethyl-benzyl-triphenylphosphonium chloride and 10 g of T-formyl-3-methyl-octa-2,6,6-triene-1-acid-butyl ester are then heated after 10 g of 1,2-butylene oxide have been added to boil with stirring, 1,2-butylene oxide is slowly distilled. The reaction mixture is stirred for 30 min. at 80-82 ° C, then cooled and extracted thoroughly with hexane. The hexane extract is shaken 5 times with 50 ml of methanol / water each time at 70:30, then dried over sodium sulfate and evaporated under reduced pressure. The remaining 9- (3-chloro-2,6, 6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1 *, 6,8-tetraene-1-acid-butyl ester can be converted to the free acid as follows: β 9- (3-Chloro-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid-butyl ester is heated in 50 ml of 5 #: ethanolic potassium hydroxide solution to boil under nitrogen gasification. The solution, which becomes clear on boiling, is cooled for 30 minutes. after, is added to water and acidified with acetic acid. Precipitated 9- (3-chloro-2,6,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,2,6,8-tetraene-1-acid melts from benzene after recrystallization at 208-209 ° C.

The starting compound 3-chloro-2,6-trimethyl-benzyl-triphenylphosphonium chloride can be prepared, for example, as follows: 119 g of chloromethylene, 11.9 g of paraformaldehyde and 5.95 g of zinc chloride (anhydrous) are heated to 60 ° C and gasified. first with stirring for 8 hours 26 62280 and after further addition of 11.9 g of paraformaldehyde for a further 8 hours with hydrogen chloride. The reaction mixture is then poured onto ice and extracted thoroughly with ether. The ether extract is washed successively with water, saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The remaining 3-chloro-2α, 6-trimethylbenzyl chloride boils after purification at 138 ° C / 17 torr.

71.25 g of 3-chloro-2,6,6-trimethylbenzyl chloride, 92 g of triphenylphosphine and 375 ml of abs. toluene is heated for 12 hours at 100 ° C. On cooling, the precipitated 3-chloro-2,6,6-trimethyl-benzyl-triphenylphosphonium chloride melts at 233-235 ° C.

Example 6

According to the procedure described in Example 7, the following can be prepared: - from 3-nitro-2,6-trimethyl-benzyl-triphenylphosphonium chloride by condensation of 7-formyl-3-methyl-hepta-2, 6,6-triene- 1-Acid-butyl ester with 9- (3-nitro-2,6, trimethyl-phenyl) -3,7-dimethyl-nona-2,6,8-tetraene-1-acid-butyl ester / oil7 ; and of which - 9- (3-nitro-2,4,6-trimethyl-phenyl) -3,7-dimethyl-nona-2α, 6,8-tetraene-1-acid, Jp. 205-206 ° C.

The starting compound 3-nitro-2α, 6-trimethyl-benzyl-triphenylphosphonium chloride can be prepared, for example, as follows: 10 g of nitromesitylene, 2 g of p-formaldehyde and 1 g of zinc chloride (anhydrous) are heated at 60 ° C with stirring. gasified for 16 hours with hydrogen chloride. The reaction mixture is then poured onto ice and extracted thoroughly with ether. The ether extract is washed successively with water, saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The remaining 3-nitro-2b, 6-trimethylbenzyl chloride, oil 22 .....

n ^ = 1.5373, further processed as follows.

11.6 g of 3-nitro-2,6-triphenylbenzyl chloride, 1 g of triphenylphosphine and 100 ml of abs. benzene is heated to reflux for 2b hours. On cooling, the precipitated 3-nitro-2,1 +, 6-trimethyl-benzyl-triphenylphosphonium chloride melts at 252-253 ° C.

Example 7

According to the procedure described in Example 7: b-methoxy-2,3,5,6-tetramethyl-benzyl-triphenylphosphonium chloride can be prepared by condensation with 7-formyl-3-methyl-octa-2,2,6-triene-1-acid butyl ester - 9- (U-Methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-nona-2,2,6,6-tetraene-1-acid-butyl ester / oil 7; and about it

2 '<6228 O

- 9- (N-methoxy-2S, N, N-tetramethyl-phenyl) -3,7-dimethyl-n-nna-2,6,6-tert-1-acid, "Jp. 239-233 ° 0 ·.: -":. 1 -LSd & öyhdi-st eena; used as U- * waste, '* - 2-, 3,' 5,6- "tetrsnnetyy 11 -benz? The following is dissolved as follows: / · "'· 15' g 2,3,5, fi-b.etra & Ethyl ^ iFeÄOpia is dissolved in 55, 3 .mu.l of methanol and, after the addition of 25 g of potassium hydroxide in 5.5 ml of water, is added at 0 to 5 ° C. -sa 'lö -., 6- = g' methyl iodide The reaction mixture is stirred for 2 seconds with others. ' temperature and ',' finally1: IS 'for 1 hour, then cool ·: .. · you go to the sound - 150 million water! 3 "of sodium hydroxide, dried over sodium sulfate 11a, and the residue is then reduced to residual 2,3 ', 5,6-tetramethylanisole by purification after adsorption. on silica gel / eluent: rheotylene nickel chloride / at 53-55 ° C, 23 g · 2,3,5,6ntetrame * y dand-sol in Ιΐ © 1-ml 'to acetic acid / water? to -5 to 293 parts of hydrochloric acid and 21.6 g of tr% are added dropwise. -; ; · .: for 3 hours, at '70 ° <7.' Wash with benzene to wash with water, then with water, dry and dry with evaporated water. 2'-Methoxy-2, R, 6,6-tert-butyl-ethyl-benzyl chloride: secreted O-formic acid ethyl ester / hexane · * 2 recrystallized, Ben-'after-lr' - '3'-äatd0. ii '* l © 5; <? (in l1. ··· v yyt' t ::,.

'E. - '28. ': oxy, β, 3,5,6-tetramethylbentyl 1 i -triphenyl ifosf is i: im chloride melts at 251-252 ° C. Example ~ vrino'vvina. 7 il "· ;, - ·. <> ·. .Example .g · -.--. ·. · .- ·· - -: -: 11. '- -::' "v · - ', -1 In E's example: / fliliaoitetj! JoinDskeii.tglytaväii- The following can be prepared: 2-5S-1H-phenyl-phthaloethyl-diphelicycliphenyl phospholium chloride from bromyl-3'-ethyl-ethyl (4-ethyl), Jil-Kapj) Ethyl-ethyl-ethyl-9 '(2', 3'-ethyl-acetyl-phenyl) -3,7'-dimethyl-nona-2,7,6,8-tetraene-1-acid-bathyl ester - (trans-phenyl) -3,7-dimethyl-r.or a- 'N ;, n, 7 ---, -.- - - 9' '(2 (69- (trans-methyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid.

Jp: 201: 7 batch used "'V-.h / - ........ - ·· - · - · - -' - '- star compound.- used 2ς · 3, ¾, 6- * t etramethyl-benzyl-triphenylphosphinium cipridia can be obtained as described in "Example" by haloformylation of "1,2,3,5-totramethyl- bmceene-2,3, N, N-tetramethyl / 1-benzynyl chloride [n, -?, ss717 28 62280 and reacting the resulting chloride with triphenylphosphine.

Example 9

According to the procedure described in Example 7, the following can be prepared: - from U-methoxy-2,6-dimethyl-benzyl-triphenylphosphonium chloride condensed with 7-formyl-3-methyl-octa-2,6-triene-1-acid butyl ester ___ (U-methoxy-2 (6-dimethyl-phenyl) -3,7-dimethyl-nona-2,6,8-tetraene-1-acid-butyl ester and from the resulting ester - 9- (4-methoxy-2,6-dimethyl-phenyl) -3 , 7-dimethyl-nona-2,6,8-tetraene-l-oic acid. Mp: 207-208 ° C.

The starting * 1-methoxy-2,6-dimethyl-benzyl-triphenylphosphonium chloride can be obtained, as described in Example 7, by haloformylating 3,5-dimethylanisole to k-methoxy-2,6-dimethylbenzyl chloride = 1.5 And reacting the resulting chloride with triphenylphosphine.

Example 10

According to the procedure described in Example 7, the following can be obtained: - from U-methoxy-3-nitro-2,6-dimethyl-benzyl-triphenylphosphonium chloride by condensation with 7-formyl-3-methyl-octa-2,2,6-triene-1-acid ethyl ester - 9 - (1,4-methoxy-3-nitro-2,6-dimethyl-phenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraene-1-acid ethyl ester and the resulting ester - 9 - (U-methoxy-3-nitro-2,2-dimethylphenyl) -3,7-dimethylnona-2,6,6,8-tetraene-1-acid. Mp: 109-110 ° C.

The starting compound U-methoxy-3-nitro-2,6-dimethyl-benzyl-triphenylphosphonium chloride can be obtained, as described in Example 7, by haloformylation of 2-nitro-3,5 "dimethyl-anisole U-methoxy-3-nitro-2,6 -dimethyl-benzyl chloride / μl: 109-110 ° C and reacting the resulting chloride with triphenylphosphine. 1 + -Methoxy-3-nitro-2,6-dimethyl-benzyl-triphenylphosphonium chloride melts at 230-232 ° C.

29 622 80

Example 11

According to the procedure described in Example T, the following can be prepared: - from 1+ ethoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride by condensation with 7-formyl-3-methyl-octa-2,6-triene-1-acid ethyl ester - 9- (U- ethoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid ethyl ester, m.p .: 96-97 ° C.

The starting compound eth-ethoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride can be obtained, as described in Example 8, by alkylation of 2,3,5-trimethylphenol to 2,3,5-trimethylphenylethyl ether (Jp: 93-95), halo-formylated ether to U-ethoxy-2,3,6-trimethyl-benzyl chloride / jp. 63-6k ° C and reacting the resulting chloride with triphenylphosphine.

Example 12

According to the procedure described in Example 7, the following can be prepared: - from L-isopropoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride by condensation with 7-formyl-3-methyl-octa-2,6-triene-1-acid butyl ester - 9- ( (-1-sopropoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraene-1-acid butyl ester and from the resulting ester - 9 - (N - isopropoxy-2,3, 6-trimethyl-phenyl) -3,7-dimethyl-nona-2, U, 6,8-tetraene-1-acid. Mp: 176-177 ° C.

The 1 + -isopropoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium bromide used as starting material can be obtained, as described in Example 8, by alkylation of 2,3,5-trimethylphenol to 2,3,5-trimethylphenylisopropyl ether (b.p. 115 ° C). 11 torr / haloformylated ether to L-isopropoxy-2,3,6-trimethylbenzyl chloride = 1.5 ^ + 33 ^ and reacting the resulting chloride with triphenylphosphine.

30 62280

Example 13

According to the procedure described in Example 7, the following can be prepared: - 3-cylime-amino-2,1 +, 6-trimethyl-benzyl-triphenylphosphonium chloride 7'-phonoyl-3-methyl-octa-2,6-6- with triene-1-acid ethyl ester - 9 '(3-dimethylamino-2,2,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,2,6-tetraene-1-acid ethyl ester ^ pale yellow oil7 · The starting compound 3-dimethylamino-2, H, 6-triraethyl-benzyl-triphenylphosphonium chloride can be obtained, as described in Example 7, by haloformylation of N, N-dimethyl-mesidine-3'-dimethylamino-2,6, 6-trimethyl to benzyl chloride / Kp. 71 ° C / 11 Torr and reacting the resulting chloride with triphenylphosphine.

Example 14 1> 7 g of 8-diethoxy-phosphono-3,7-dimethyl-octa-2,2,6-triene-1-acid ethyl ester are dissolved in 8.0 ml of tetrahydrofuran. 0.27 g of sodium hydride from 50-60 ° C are added to the solution at 0 ° C, stirred for 30 min. at 0 ° C and then added dropwise over 15 min. containing a solution of 0.96 g of 2,3,6-triraethyl-p-anisaldehyde in 3 ml of tetrahydrofuran. The reaction mixture is stirred for 7 hours at room temperature, then poured onto ice and, after addition of 2N hydrochloric acid, extracted with ether. The ether extract is washed neutral with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 9- (N-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,6,8-tetraene-1-acid ethyl ester melts at 10-14-105 ° C.

Instead of the sodium hydride 0,0.27 ff used above, it is also possible to use an alkali metal alcoholate α, e.g.

The starting 8-diethoxy-phosphono-3,7-dimethyl-octa-2,6,6-triene-1-acid ethyl ester can be prepared, for example, as follows: 3.03 g of 8-bromo-3,7-dimethyl-octa -2, b, 6-Triene-1-acid ethyl ester is slowly heated together with 1.66 g of triethyl phosphite at 125 ° C. The excess bromoester is distilled off. After cooling, the residue is poured onto ice and extracted with ether. The ether extract is washed with water and saturated aqueous sodium hydrogen carbonate solution, dried and evaporated under reduced pressure. The remaining 8-diethoxy-phosphono-3,7-dimethyl-octa-2,1 +, 6-triene-1-acid-ethyl ester is reacted immediately with 2,3,6-trimethyl-p-anisaldehyde as described above.

31 62280

Example 15 A) 2 g of 1- (phenylsulfonyl) methyl-N-methoxy-2,3,6-trimethylbenzene are dissolved in 10 ml of tetrahydrofuran. The solution is cooled to -6 ° C and after the addition of 0.51 g of butyllithium a solution of 1.8 g of 8-bromo-3,7-dimethylocta-2,6-triene-1 acid ethyl ester in 8 ml of tetrahydrofuran. The reaction mixture is stirred for 2 hours at 7878 ° C, for a further 2 hours at ^0 ° C, and finally for 16 hours at 0 to + 5 ° C. The mixture is then poured onto ice and, after addition of 2N hydrochloric acid, extracted with ether. The ether extract is washed with water neutrally, dried over sodium sulfate and evaporated under reduced pressure. Residual 9- (N-methoxy-2,3,6-trimethyl-phenyl) -9- (phenylsulfonyl) -3,7-dimethyl-nona-2,4,6-triene-1-acid ethyl ester (2.8 g) is dissolved in 8 ml of abs. ethanol. A total of 1.2 g of sodium ethylate powder is added to the solution at 0 ° C in 2 portions. The mixture is first stirred for 30 min. for 1 hour at 0 ° C, then for 2 hours at 80 ° C, then cooled, poured onto ice and, after addition of 2N hydrochloric acid, extracted with ether. The ether extract is washed neutral with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 9- (N-netoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1 *, 6,8-tetraene-1-acid ethyl ester melts at 10 + 1 -105 ° C. .

The starting 1- (phenylsulfonyl) methyl-k-methoxy-2,3,6-trimethylbenzene can be prepared, for example, as follows: 16.8 g of U-methoxy-2,3,6-trimethylbenzyl alcohol, 17 1 g of the Na salt of benzenesulphonic acid, 20.0 ml of isopropanol and 30.0 ml of glacial acetic acid are heated under reflux under nitrogen for 16 hours. After cooling, 200 ml of water are added portionwise to the reaction mixture and neutralized by adding sodium hydrogencarbonate. The organic phase is separated, washed several times with 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The remaining 1- (phenylsulfonyl) methyl-U-methoxy-2,3,6-trimethylbenzene has the following I-R bands: 1592, 1580, 1302, 11U9, 1113 cm-1.

B) 1.08 g of N-methoxy-2,3,6-trimethylbenzyl chloride, 1.67 g of 8- (phenylsulfonyl) -3,7-dimethylocta-2,6, tri-triene-1-yl the acid ethyl ester and 10 ml of dimethylformamide are cooled to 0 [deg.] C. and 0.37 g of solid sodium ethanolate are added. The reaction mixture is stirred for 30 min. at room temperature, then poured onto ice and, after addition of 2N hydrochloric acid, extracted with ether. The ether extract is washed neutral with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 9 ′ ′ (n-hydroxy-2,3,6-trimethyl-phenyl) -8- (phenyl-

32 '6228C

sulfonyl) -3,7-dimethyl-nona-2,1,6-triene-1-acid ethyl ester is modified as described in A) by cleaving the benzenesulfinic acid and forming the additional carbon-carbon bond to the desired 9 "(k-methoxy-2, 3,6-Trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid ethyl ester [3β. 10l4-105 ° c7.

The starting compound 8- (phenylsulfonyl) -3,7-dimethylocta-2,2,6-triene-1-acid ethyl ester can be prepared, for example, as follows: 3.5 g of 8-bromo-3,7-dimethylocta-2 The 1,6-triene-1-acid ethyl ester is dissolved in 95 ml of dimethyl sulfoxide. 45 g of the sodium salt of benzenesulphonic acid are added to the solution under a nitrogen atmosphere in the cold. The mixture is stirred for 1 hour at room temperature, then poured onto ice and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 8- (phenylsulfonyl) -3,7-dimethylocta-2,6-triene-1-acid ethyl ester melts at LiU-115 ° C.

Example 16 60 g of 9- (1- + methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid are dissolved in 1000 ml of acetone. The solution is stirred after the addition of 128 g of methyl iodide and 128 g of potassium carbonate under nitrogen gasification for 16 hours at 55-60 [deg.] C. and finally evaporated under reduced pressure. The residue is dissolved in 1300 ml of petroleum ether / boiling point 80-105 ° ς}. 9- (U-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2, k, 6,8-tetraene-1-acid methyl ester, which crystallizes at -20 ° C, melts 98-99 ° C.

In a similar manner there are obtained: - 9- (H-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2, b, 6,8-tetraene-1-acid and ethyl iodide 9- (14-methoxy- -2,3,6-Trimethyl-phenyl) -3,7- (dimethyl-nona-2,1,6,8-tetraene-1-acid ethyl ester Jp: 10U-105 ° C 1-9- (L-methoxy-2 From 3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid and isopropyl iodide - 9 "(U-methoxy-2,3,6-trimethyl-phenyl) ) -3,7-Dimethyl-nona-2H, 6,8-tetraene-1-acid isopropyl ester 9 '(N-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl- from nona-2,2,6,6-tetraene-1-acid and ethyl iodide - 9- (U-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-nona-2, U, 6,8-Tetraene-1-acid ethyl ester, mp: 105-106 ° C; - 9 '(N-ethoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2 From U, 6,8-tetraene-1-acid and diethylaminoethyl chloride - 9 '(U-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2, U, 6,8-tetraene -1- 33 622 80 Acid-2- (diethylamino) -ethyl ester ester oil-9 ~ (1 * -meth) oxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid and N-picoline chloride - 9 - (N-methoxy-2,3, 6-Trimethyl-phenyl) -3,7-dimethyl-nona-2, h, 6,8-tetraene-1-acid (3-pyridyl) -methyl ester, mp: 113-11 ° C.

Example 17 20 g of 9 '(U-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,2,6-tetraene-1-acid are dissolved in 200 ml of tetrahydrofuran. The solution is stirred after the addition of 5 to 5 l of phosphorus trichloride for 2 hours at room temperature, then cooled to 0 [deg.] C., first 50 ml of pyridine are added and then 50 ml of propargyl alcohol are added dropwise at 0-5 [deg.] C. The mixture is stirred for 2 hours at room temperature and finally diluted with water. The organic phase is washed successively with water, dilute hydrochloric acid and 2%: 11b. aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated. The remaining 9- (N-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraenoic acid propargyl ester melts after adsorption on alumina. ^ 9 ~ 95 ° C.

In a similar manner there are obtained: - 9- (14-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid and allyl alcohol - 9- (U-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,2,6,8-tetraene-1-acid allyl ester, Jp. 66-68 ° C.

Example] 28.6 g of 9- (N-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraene-1-acid are added in 300 ml. in benzene and 12 g of phosphorus trichloride are added under nitrogen gasification. Benzene is finally distilled under reduced pressure. The remaining 9- (N-methoxy-2,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,6,6,8-tetraene-1-acid chloride is dissolved in 1200 ml of ether. The solution is added dropwise at -33 ° C to 500 ml of liquid ammonia and stirred for 3 hours. The reaction mixture is then diluted with 500 ml of ether and stirred further without cooling for 12 hours, at which time the ammonia evaporates. The residue is dissolved in 10 liters of methylene chloride. The solution is washed twice with 3 liters of water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 9- (1 + -methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,1,6,8-tetraene-1-acid amide melts after recrystallization from ethanol at 207-209 ° C: in.

34 6 2 2 8 0 In a similar manner there are obtained: - 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid chloride and ethylamine-9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid-ethylamide; Jp. 179-180 ° C; - 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid chloride and diethylamine - 9- (4-methoxy- 2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-l-acid diethylamide; Jp. 105-106 ° C; - 9- (4-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid chloride and ethylamine - 9- (4- methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid-ethylamide, mp: 200-201 ° C; - 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid chloride and morpholine - 9- (4-methoxy- 2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid morpholide, m.p. 141-142 (from a mixture of bentene and hexane).

Example 19 15 g of a mixture of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid ethyl ester / Chromatograph with 1.5 kg of alumina. Activity step XJ / Celling agent: hexane / ether 80: 207. 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2-trans, 4-cis, -6-trans, 8-trans-tetraene-1- isolated from the first step acid ethyl ester is a pale yellow oil ·

Example 20

According to the procedure described in Example 4, 4-methoxy-2,6-dimethyl-3-ethylbenzyltriphenylphosphonium chloride can be prepared by reacting it with 7-formyl-3-methylocta-2,4,6-triene-1-acid ethyl ester 9- (4- Methoxy-2,6-dimethyl-3-ethylphenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid ethyl ester, which by saponification gives 9- (4-methoxy-2,6- -dimethyl-3-ethylphenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid, mp 19-198 ° C.

The starting material 4-methoxy-2,6-dimethyl-3-ethylbenzyl-triphenylphosphonium chloride can be prepared in a similar manner to the previous examples, for example, from 3,5-dimethylphenol to give 1-acetoxy-3,5-dimethylbenzene to give 2-acetyl- 3,5-Dimethylphenol to give 2-ethyl-3,5-dimethylphenol to give 62280 to give 2-ethyl-3,5-dimethylanisole to give 4-methoxy-2,6-dimethyl-3 -etyylibentsyylikloridi.

Example 21

According to the procedure described in Example 4, 4-methoxy-3,5-diethyl-2,6-dimethylbenzyltriphenylphosphonium chloride can be prepared by reacting it with 7-formyl-3-methylocta-2,4,6-triene-1-acid ethyl ester 9- ( 4-Methoxy-3,5-diethyl-2,6-dimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid-ethyl ester, which by saponification gives 9- (4-methoxy-3-acid , 5-diethyl-2,6-dimethylphenyl) -3,7-dimethylnona-2,4,6,6-tetraene-1-acid, m.p.

15-154 ° C.

The starting 4-methoxy-3,5-diethyl-2,6-dimethyl-benzyltriphenylphosphonium chloride can be prepared in a manner similar to the previous examples, for example, from 3,5-dimethylphenol to give 1-acetoxy-3,5-dimethylbenzene to give 2-acetyl- 3,5-Dimethylphenol to give 2-ethyl-3,5-dimethylphenol to give 1-acetoxy-2-ethyl-3,5-dimethylbenzene to give 6-acetyl-2-ethyl-3,5-dimethylphenol to give 2,6-Diethyl-3,5-dimethylphenol to give 2,6-diethyl-3,5-dimethylanisole to give 4-methoxy-3,5-diethyl-2,6-dimethylbenzyl chloride.

Example 22

According to the procedure described in Example 4, 4-propoxy-2,3,6-trimethylbenzyltriphenylphosphonium chloride can be prepared by reacting it with 7-formyl-3-methylocta-2,4,6-triene-1-acid ethyl ester 9- (4- propoxy-2,3,6-trimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid ethyl ester, which is saponified to give 9- (4-propoxy-2,3,6-trimethylphenyl) - 3,7-dimethyl-linona-2,4,6,8-tetraene-1-acid, ip. 200-201 ° C.

The starting material 4-propoxy-2,3,6-trimethylbenzyltriphenylphosphonium chloride can be prepared in a similar manner to the previous examples, for example, from 2,3,5-trimethylphenol to give 2,3,5-trimethylpropoxybenzene to give 4-propoxy-2,3,6- t * i-methylbenzylchloride.

Example 23

According to the procedure described in Example 4, 4-ethoxy-2,3,6-trimethylbenzyltriphenylphosphonium chloride can be prepared by reacting it with 7-formyl-3-methyl-ε-2,4,6-triene-1-acid ester 9- ( 4-ethoxy-2,3,6-trimethylphenyl) -3,7-35,622,810 dimethylnona-2,4,6,8-tetraene-1-acid ethyl ester obtained by saponification of 9- (4-ethoxy-2, 3,6-trimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid, m.p. 219-220 ° C.

3,5-Dichloro-2,4,6-trimethylbenzyltriphenylphosphonium chloride can be prepared by reacting it with 7-formyl-3-methyl-octa-2,4,6-triene-1-acid ethyl ester 9- (3,5-dichloro). - 2,4,6-Trimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid ethyl ester obtained by saponification of 9- (3,5-dichloro-2,4,6-trimethylphenyl) -3,7-dimethylninone-2,4,6,8-tetraene-1-acid, m.p. 220-222 ° C.

Example 24

According to the procedure described in Example 4, 3-chloro-2,4,6-trimethylbenzyltriphenylphosphonium chloride can be prepared by reacting it with 7-formyl-3-methylocta-2,4,6-triene-1-acid ethyl ester 9- (3-chloro). 2,4,6-Trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-acid-ethyl ester, ip. 84-85 ° C.

The starting 3-chloro-2,4,6-trimethylbenzyltriphenylphosphonium chloride can be prepared in a manner similar to the previous examples, for example, 2,4,6-trimethylaniline to give 2,4,6-trimethylchlorobenzene, to give 3-chloro-2,4,6- trimethylbenzyl chloride to give the desired compound.

Example 25 36.5 g of 1-ethoxycarbonyl-2,6-dimethylhepta-1,3,5-triene-7-triphenylphosphonium bromide are dissolved in 200 ml of dimethylformamide. To the solution is added 15.0 g of 4-methoxy-3-butyl-2,6-dimethylbenzaldehyde, cooled to 10 ° C, 1.64 g of 40 abs. ethanol dissolved in sodium and then stirred for 12 hours at room temperature. The reaction mixture is poured into 500 any methanol / water 60:40. The methanol / water phase is extracted with hexane. The hexane extract is washed first with methanol / water 60t40, then with water, dried over sodium sulfate and evaporated to dryness. The remaining 9- (4-methoxy-3-butyl-2,6-dimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid ethyl ester is saponified as described in Example 1. The obtained 9- (4-methoxy-3-butyl-2,6-dimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid melts at 147-148 ° C.

The starting 4-methoxy-3-butyl-2,6-dimethylbenzaldehyde can be prepared, for example, as follows: 294 2 ml of concentrated sulfuric acid are added and then 122 g of 3,5-dimethylphenol are added at room temperature. Initially, the temperature rising to about 40 ° C 37 622 8 0 is raised to 80 ° C. After 1 hour, the reaction mixture is diluted with 60 ml of water and 60 ml of ethanol. The mixture is stirred for 30 minutes, the mixture is poured into ice water and washed twice with 500 ml of hexane each time. The hexane extract is washed alternately with water and saturated aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to dryness. The remaining 1-butyryloxy-3,5-dimethylbenzene boils after concentration distillation at 123-125 ° C / 11 torr.

To 180 g of 1-butyryloxy-3,5-dimethylbenzene is added 340 g of aluminum chloride. The reaction mixture is then stirred for 4 hours at 90-95 ° C *. After the temperature has dropped to 70 ° C, the mixture is poured into a mixture of ice and 3N hydrochloric acid and extracted with ether. The ether extract is washed with water until neutral, dried over sodium sulfate and evaporated to dryness. The remaining 2-butyryl-3,5-dimethylphenol melts after recrystallization from petroleum ether at 48-52 ° C.

10 g of 2-butyryl-3,5-dimethylphenol are dissolved in 100 ml of glacial acetic acid. 0.5 g of platinum oxide and 3 drops of 70% perchloric acid are added to the solution and hydrogenated under normal conditions, when the hydrogen uptake is 3.0 l, the hydrogenation is stopped. The catalyst is filtered off.

The filtrate is extracted with ether. The ether extract is washed with water until neutral, dried over sodium sulfate and evaporated to dryness. The residual 2-butyl-3,5-dimethylphenol is purified by adsorption on silica gel (eluent methylene chloride / hexane 1: 1), m.p. 65-67 ° C.

83 g of 2-butyl-3,5-dimethylphenol are dissolved in 255 ml of methanol. To the solution is added 60 g of potassium hydroxide dissolved in 25 ml of water and then dropwise 34.2 ml of methyl iodide. The reaction mixture is heated to reflux for 3 hours. The mixture is cooled, diluted with water and extracted with ether. The ether extract is washed with dilute sodium hydroxide, dried over sodium sulfate and evaporated to dryness. The remaining 2-butyl-3,5-dimethylanisole is purified by adsorption on silica gel (eluent: hexane / methylene chloride 70:30) and further treated as follows: 5.5 ml of phosphorus oxychloride are added dropwise with stirring to 4.6 ml of dimethylformamide at 20 ° C: in. The temperature then rises to 30 ° C. 9.6 g of 2-butyl-3,5-dimethylanisole are added dropwise to the mixture, the mixture is then heated to 100-115 ° C for 4 hours and poured into ice water.

A 30-35% aqueous sodium acetate solution is added to the mixture, the mixture is then stirred for 1 hour and the mixture is extracted with benzene. The benzene extract is washed with water, dried over sodium sulfate and evaporated to dryness. The remaining 4-methoxy-3-butyl-2,6-dimethylbenzaldehyde-62s 62280 hyd is purified by adsorption onto silica gel (eluent: hexane / methylene chloride 1: 1) and condensed with 1-ethoxycarbonyl-2,6-dimethylhepta-1,3, With 5-triene-7-triphenylphosphonium bromide.

1-Ethoxycarbonyl-2,6-dimethylhepta-1,3,5-triene-7-triphenylphosphonium bromide condensable with 1 + -methoxy-3-butyl-2,6-dimethylbenzaldehyde can be prepared, for example, as follows: 36 g of 7-formyl-3-methylocta-2 , h, 6-triene-1-acid ethyl ester is added to 600 ml of abs. ethanol. 1.8 g of sodium borohydride are added portionwise to the cloudy solution at 10 ° C and the mixture is stirred for 2 hours at 10 ° C. The reaction mixture is poured into ice water, and 3N hydrochloric acid is added to this mixture. The mixture is extracted with ether. The ether extract is washed with water, then with saturated aqueous sodium bicarbonate solution and then again with water, dried and evaporated to dryness. The remaining 8-hydroxy-3,7-dimethylocta-2,4,6-triene-1-acid ethyl ester is further treated as follows: 36.8 g of 8-hydroxy-3,7-dimethylocta-2, h, 6-triene-1 The acid ethyl ester is dissolved in 380 ml of ether. The solution is cooled to 0 ° C, first 3 drops of pyridine are added dropwise and then a solution of 28.6 g of phosphorus tribromide and 120 ml of hexane. The reaction mixture is stirred for 20 minutes at 0 ° C, the mixture is poured into ice water and extracted with ether. The ether extract is washed with water, then with saturated aqueous sodium bicarbonate solution and then again with water, dried and evaporated to dryness. The remaining 8-bromo-3,7 "dimethylocta-2,2,6-triene-1-acid ethyl ester is further treated as follows: ^ 3.7 g of 8-bromo-3,7-dimethylocta-2,6-triene-1- The acid ethyl ester is dissolved in 500 ml of benzene and U2.0 g of triphenylphosphine are added to the solution, the reaction mixture is stirred for 12 hours at room temperature and then cooled to 0 [deg.] C. 1-Ethoxycarbonyl-2,6-dimethylhepta-1,3,5-triene precipitates. - 7-triphenylphosphonium bromide, mp 193-19 ° C.

Example 26

According to the procedure described in Example 2k, 9- (1 + -methoxy-2,3,6-trimethylphenyl) -3,7-dimethylnona-2,1,6,8-tetraene-1-acid chloride can be prepared by reacting it with methylamine 9- (14- methoxy-2,3,6-trimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid methylamide, m.p. 206 ° C.

From the starting material mentioned at the beginning of the example, it is obtained by reacting it with isopropylamine 9- (ii-methoxy-2,3,6-trimethylphenyl) -3,7-dimethylnona-2,6,6,8-tetraene-1-acid isopropylamide, i. 200 ° C.

Said starting material is obtained by reacting it with n-butylamine 9- (U-methoxy-2,3,6-trimethylphenyl-3,7-dimethylnona-2,6,8-tetraene-1-acid-n-butylamide, ip. 178 ° C.

Said starting material is obtained by reacting it with hexylamine 9- (N-methoxy-2,3,6-trimethylphenyl) -3,7-dimethylnona-2, k, 6,8-1-acid-hexylamide, ip. 157-158 ° C. ; 39 62280

Example 27 9- (II-Methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,1,6,8-tetraen-1-ol was added to 150 g of 9- (4-methoxy- 2,3,6-Trimethylphenyl-3,7-dimethyl-2,7,6,8-nona-tetraene-1-acid ethyl ester is added to 800 ml of toluene and the mixture is stirred until all the solid has dissolved. To 60 [deg.] C. At this temperature, 780 ml of a 25 ~ solution solution of diisobutylaluminum hydride are added dropwise to the solution. The temperature of the reaction mixture gradually rises to + 10 [deg.] C. 1 [mu] l of saturated aqueous sodium sulphate solution is added dropwise to the mixture, and the temperature is allowed to rise to +25 [deg.] C. 300 ml of chloroform are added and the mixture is stirred for a few more minutes filtration aid, the precipitate is filtered off and washed U times with 500 ml of chloroform each time. The combined filtrates are washed successively with 600 ml of water, 600 ml of water containing 10 ml of 3N hydrochloric acid, 600 ml of saturated aqueous sodium bicarbonate solution and 600 ml of water and then dried over anhydrous sodium sulfate and evaporated to dryness. The crystalline residue is taken up in 1000 ml of hot hexane with vigorous stirring. A yellow 9- (N-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,4,6,8-tetraen-1-ol crystallizes from solution and is washed with hexane and dried, which melts first at 10-15 torr, then at 0.5 torr at 127.5 ~ 129.5 ° C.

Example 28 Methyl ether of 9- (U-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraen-1-ol

To a mixture of 156 g of 9- (n-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,1 +, 6,8-tetraen-1-ol, 56 g of methyl iodide and 2.5 l of tetrahydrofuran is added with stirring at 20-25 ° C over one hour to g of sodium hydride. After a few minutes, the temperature of the mixture rises to 28 ° C and is lowered externally to 25 ° C. The resulting yellow solution is cooled to 10 ° C. Excess sodium hydride is decomposed by dropwise addition of a 50- $ aqueous solution of methanol. The solvent is distilled off to give a semi-crystalline residue which is dissolved in 500 ml of benzene. The solution is washed three times with 500 ml of saturated aqueous sodium bicarbonate solution and once with water to which a little 40 62280 sodium sulphate has been added. To the solution is added 100 mg of 2,6-di-tert-butyl-p-cresol, the solution is dried over anhydrous sodium sulfate and evaporated to dryness. The syrupy residue is taken up in 350 ml of hot hexane. The mixture is filtered under nitrogen. Within one hour at 0 ° C, a crystalline methyl ether of 9- (N-methoxy-2,3,6-trimethyl-phenyl) -N, N-methyl-nona-?-Tetraen-1-ol precipitates from the filtrate, which is washed with hexane and dried The melting point of the compound is initially at 10-15 torr and then at 0.5 torr at 67.5-69.5 ° C.

Example 29 9- (1 + -Methoxy-2,3,6-trimethylphenyl) -3,7-nona-2,1 *, 6,8-tetraen-1-ol n-butyl ether 6.0 g of 9- (it- methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2,6, 6,8-tetraen-1-ol is dissolved in a solution of 28.05 g of n-butyl iodide in 150 ml of tetrahydrofuran. 0.92 g of sodium hydride is added to the solution and stirred for U8 hours. Excess sodium hydride is decomposed in the cold by careful addition of methanol. The reaction mixture is diluted with 500 ml of water and extracted three times with 50 ml of ether each time. The extract is dried over magnesium sulfate and evaporated to dryness. The residue is taken up in 10 ml of hexane. 10 ml of methanol are added to precipitate 2.5 g of starting material (pour point 107-112 ° C), which is filtered off. The filtrate is evaporated to dryness. The yellow crystalline residue is n-butyl ether of 9- (1 + -methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nona-2, k, 6,8-tetraen-1-ol. The compound is purified by adsorption on 200 g of silica gel (eluent ether / hexane 50:50). The m.p. is 52-5 ° C.

Claims (4)

1. Analogous process for the preparation of tumor-inhibiting polyene compounds of formula I2 in R5 wherein R and R2 are lower alkyl; R 2 is hydrogen, lower alkyl, halogen, nitro, amino, di-lower alkylamino mono; R 2 is hydrogen, lower alkyl, lower alkoxy or lower alkoxy; R ,. is hydrogen or lower alkyl, under reservation, that at least one of the radicals R are lower alkyl, they represent two other non-hydrogen at the same time, and when R 7 is halogen, R 2 is (not alkoxy; and R -alkylcarbamoyl, morpholinocarbonyl or 3-pyridylmethyleneoxycarbonyl, and their salts, characterized in that either a) a phosphonium salt of formula (-) r 2 - R 5 or a phosphonate of formula 0 " 3. In n (Hb) Rr S 3 O - J (Ile) -R 1 R 5 is reacted with a phosphonium salt of formula R '7 rJS Θ (nib) FOY Ϊ or a phosphonate of formula wj (IIIc) 0 or c) SO E} - I η! (ΙΜ) r 5 is reacted with a compound of formula (Hid) B or d) a compound of formula ** Hm '3 (He) R 1 - R 1 r 5 is reacted with a sulfon of formula SO2E (1IIe) n represents an integer 0 or 1 and n + m = 1; X is aryl and Y is an arion of an organic or inorganic acid; Z is alkoxy; E is an aryl or aralkenyl radical which may be substituted by one or more electrons rebel or electrons weakly attracting groups; B is halogen, alkylsulfonyloxy or arylsulfonyloxy; and Rj. above has n meaning; is carboxyl, alkoxycarbonyl,