BG60406B2 - 9-phenyl-nonate traen compounds - Google Patents

Abstract

The compounds can be effectively used as antitumour agent, as well as for the treatment of acne, psoriasis and other dermatological diseases. They are of low toxicity. The compounds are 9-phenyl-5, 6-dimethyl-nona-2,4,6,8-tetraenic acids, tetraenal or tetraenol derivatives.

Description

SUMMARY OF THE INVENTION It has been found that the compounds of formula:

wherein R 1 and R ₂ are lower alkyl, R ₃ is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, nitro, halogen, amino, lower alkylamino group, lower alkanoylamino group or N-heterocycle; R ₄ is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, lower alkanoyloxy, amino, lower alkylamino, or a heterocyclic radical; R ₃ means hydrogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, halogen, amino, lower alkanolamino, lower alkylamino or N-heterocyclic radical provided that at least one of R 1, R ₄ and R ₃ is other than hydrogen and further provided that when R 1 or R ₃ is halogen, R ₄ is other than alkoxy, R ₆ is formyl, hydroxymethylene, alkoxymethylene, alkanoyloxymethylene, carboxyl alkoxycarbonyl, alkenyloxycarbonyl, alkinyloxycarbonyl, carbamoyl-mono (nyc) -alkyl-mono (alkyl) carbamoyl, di (lower alkyl) -carbamoyl or Nheterocyclylcarbonyl; or pharmaceutically acceptable salts thereof, which are useful as antitumor agents.

The compounds of formula I are prepared by reacting a compound of formula:

with a compound of formula:

wherein R 1, R 1, R ₃ , R ₄ and R ₃ have the meanings given above; mu η are integers from 0 to 1, with the sum of mu η being 1, one of the substituents A or B being oxo and the other:

-Ρ / Χ /, + y- η -P / Z /, or

O o II one of ABi - S - R.

Y * and the other is halogen, alkylsulfonyloxy or arylsulfonyloxy; X is aryl, Z is alkoxy, Rj ₀ is aryl, aralkenyl, aryl substituted with electron-donating or electron-withdrawing group or aralkenyl wherein the aryl radical is substituted with an electron-withdrawing or electron-donating group or an aralkenyl wherein the aryl moiety is substituted by an electron-attracting or electron-donating group; R ₇ where

Oh

II

B is -Ρ- (Ζ) ₂ or -S- R ₂₀ or

I II about

-P / X / ₃ ⁺ Y ', is formyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkinyloxycarbonyl, di (lower alkyl) carbamoyl or N-heterocyclylcarbonyl; R ₇ when B is oxo, carboxy, alkoxymethylene, alkanoyloxymethylene, alkoxycarbonyl, alkenyloxycarbonyl, alkinyloxycarbonyl or N-heterocyclylcarbonyl; R ₇ when B is halogen, alkylsulfonyloxy or arylsulfonyloxy, is formyl, carboxy, alkoxymethylene, alkanoyloxymethylene, alkoxycarbonyl, alkenyloxycarbonyl, alkinyloxycarbonyl, di (lower alkyl) -amino-carbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoylcarbamoyl

In the case where one of A or B forms a sulfone group containing a sulfone group:

Oh

o it can be in the reaction product

is separated as a double bond to form a compound of formula I. The reaction product is a compound of formula II and III, wherein R ₇ is a carboxyl group that can be esterified or amidated. On the other hand, when R 1 is a carboxyl or ester group, the reaction product may be reduced to form R ₇ as a hydroxyl group. When the reaction product contains R ₇ as a hydroxyl group, it can be esterified or esterified. The resulting alcohol ester can, if desired, be saponified. On the other hand, when in the reaction product R ₇ is a free hydroxyl or ester group, this product may be oxidized to form the corresponding compound wherein R 1 is a carboxyl group, i.e.-COOH.

In the present invention, the term "halogen" means the four halogen elements; ie chlorine, bromine, iodine and fluorine, with chlorine and bromine being preferred. The term "lower alkyl" means straight or branched chain lower alkyl groups containing from 1 to 6 carbon atoms such as methyl, ethyl, isopropyl and 2-methylpropyl. The term "lower alkyloxy" as used herein means a lower alkoxy group containing from up to 7 carbon atoms such as methoxy, propoxy, isopropoxy, ethoxy, etc. The term "lower alkanoyl" means a lower alkanoyl group containing from 2 to 6 carbon atoms such as acetyl, propionyl or pivaloyl group.

The terms "lower alkenyl" and "lower alkynyl" include straight- or branched-chain carbon groups containing from up to 6 carbon atoms such as vinyl, allyl, butenyl, pentenyl, ethynyl, propargyl, butynyl, etc.

The term N-heterocyclic means N-heterocyclic radicals, preferably containing a 5 to 6 membered ring, which have a nitrogen atom in the ring and which may optionally contain another heteroatom selected from the group of oxygen, nitrogen or sulfur. Among the preferred radicals are pyrrolidine, pyridine, piperidine, morpholine or thiomorpholine.

The lower alkanoylamino groups contain residues derived from the lower alkanecarboxylic acids containing from 2 to 6 carbon atoms (eg acetic, propionic or pivalic acid).

The alkoxymethylene and alkoxycarbonyl groups preferably contain alkoxy moieties having from 1 to 6 carbon atoms. They may be straight or branched, for example methoxy, ethoxy and isopropoxy groups. The alkoxy moiety may also be a higher alkoxy group containing from 7 to 20 carbon atoms, in particular the cetyloxy group. The alkoxy moiety may be substituted by functional groups, for example, nitrogen-containing groups such as an amino or morpholine group, which may be alkyl substituted, or by a piperidyl or pyridyl group.

Alkenyloxycarbonyl and alkynyloxycarbonyl groups preferably contain alkenyloxy and alkynoxy moieties having 2 to 6 carbon atoms, such as an allyloxy or proparglyloxy group.

The term "alkanoyloxy" means alkanecarboxylic acid derivatives containing from 2 to 20 carbon atoms. Among the preferred lower alkanoyloxy groups are the lower alkanoyloxy groups of 2 to 6 carbon atoms, for example acetyloxy, propionyloxy and pivalyloxy groups. In addition, the alkanoyloxy group may be derived from higher alkanecarboxylic acids, i. E. from acids containing from 6 to 20 carbon atoms such as palmitic acid or stearic acid, as well as lower alkanoyloxy groups. The term "alkanoyloxymethylene" means alkanoyloxymethylene groups in which alkanoyloxy has the meanings indicated above. Among the preferred alkanoyloxymethylene groups are acetyloxymethylene and propionyloxymethylene.

The terms "mono" and "di (lower alkyl) carbamoyl" mean mono and di (lower alkyl) carbamoyl radicals in which lower alkyl has the meanings indicated above. Among the preferred mono and di (lower alkyl) carbamoyl groups are N-methyl-carbamoyl, N, N-dimethylcarbamoyl, N-isopropylcarbamoyl, and N-tert-buticarbamoyl. "N-heterocyclylcarbonyl radicals" are those which preferably contain a 5 or 6 membered heterocyclic ring which, in addition to the nitrogen atom, may also contain another heteroatom selected from nitrogen, oxygen or sulfur. Examples of such N-heterocyclic groups that can be used according to the invention are the pyridino, piperidino, morpholino, thiomorpholino and pyrrolidine groups.

For the compounds of formula I, preferred di (lower alkyl) amino groups are those wherein the lower alkyl substituent contains from 1 to 4 carbon atoms. Preferred lower alkylamino groups are ethylamino, dimethylamino, diethylamino and diisopropylamino. The term lower alkylamino radical includes both mono- and di-lower alkylamino groups.

Among the preferred compounds of formula I are:

9- (2,3,6-trimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid;

9- (2,4,6-trimethylphenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid;

9- (2,4,6-triisopropylphenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acid;

9- (2,3,4,6-methyltetrophenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acic acid;

9- (4-Methoxy-2,6-dimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-one acid;

9- (4-Methoxy-2,3,6-trimethylphenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acid;

9- (3-methoxy-2,4,6-trimethylphenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acid;

9- (4-Methoxy-2,3,6-trimethylphenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acid ethyl ester;

9- (4-Methoxy-2,3,6 trimethylphenyl) -3,7-dimethyl-non-2-trans, 4 cis, 6-trans, 8-trans-tetraene-1-acid ethyl ester;

9- (4-Methoxy-2,3,6 trimethylphenyl) -3,7-dimethyl-non-2,4,6,8tetraen-1-acid isopropyl ester;

9- (4-Methoxy-2,3,6-trimethylphenyl) -3,7-dimethylnona-2,4,4,8-tetraen-1-one acid diethylaminoethyl ester;

9- (4-Methoxy-2,3,6 trimethylphenyl) -3,7-dimethyl-nona-2,4,6,8tetraen-1-acid acid amide;

9- (4-Methoxy-2,3,6 trimethylphenyl) -3,7-dimethyl-nona-2,4,6,8tetraen-1-acid ethylamide;

9- (4-Methoxy-2,3,6 trimethylphenyl) -3,7-dimethyl-nona-2,4,6,8tetraen-1-acid allyl ester;

9- (4-methoxy- propargyl ester)

2.3.6-trimethylphenyl) -3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid;

9- (3,6-dimethoxy-2,4,5-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid;

9- (4-Methoxy-3-allyl-2,6-dimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid;

9- (4-Methoxy-3-nitro- ethyl ester)

2,6-dimethylphenyl) -3,7-dimethylnona-2,4,6,8tetraene-1-acid;

9- (3-Dimethylamino- ethyl ester)

2.4.6-trimethylphenyl) -3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid;

9- (4-Isopropoxy-2,3,6 trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid;

9- (4-allyloxy-2,3,6-trimethylphenol) -

3.7-dimethyl-non-2,4,6,8, -tetraene-1-acid;

9- (5-chloro-2,4,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-one acid and

9- (3-Nitro-2,4,6-trimethylphenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acid.

The compounds of formula I have low toxicity. For example, as can be seen from the following table, the acute toxicity (LD _R) of 9- (4-methoxy-2,3,6-trimethylphenyl) -

The 3- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethylnon-2-3,7-dimethyl-non-2,4,6,8-tetraen-1-one acid (A) and ethyl ester, 4,6,8-tetraene-1-acid (B) in mice after intraperitoneal administration of the compound in rapeseed oil was 700 or 1000 mg / kg.

Table

Substance A Acute toxicity LD ₁₀ mg / kg LD ₅₀ mg / kg ld _m mg / item after 1 day > 4000 > 4000 > 4000 after 10 days 580 700 890 after 20 days 580 700 890 Substance B. LD ₁₀ mg / kg LD ₅₀ mg / kg LD _M mg / Art after 1 day > 4000 > 4000 > 4000 after 10 days 1400 1900 2600 after 20 days 710 1000 1400

The compounds of formula I are effective in treating tumors such as papilloma. In the papilloma test, tumors induced with dimethylbenzanthracene and croton oil regressed in development. The papilloma diameter decreases within two weeks after intraperitoneal administration. For substance A, the reduction was 38% at 50 / mg / kg / week and 69% at 100 mg / kg / week, and for substance B the reduction was 45% at 25 mg / kg / week and 63% at 50 mg / kg / week.

The compounds of formula I are also useful drugs for the topical and systemic treatment of acne, psoriasis and other related dermatological diseases, which are characterized by increased or pathologically altered keratinization, as well as inflammatory and allergic dermatological conditions. They can also be used to treat conditions characterized by inflammatory or degenerative changes in the mucous membranes.

The polyene compounds of formula I may be used as medicaments, for example in the form of pharmaceutical preparations containing them together with a compatible pharmaceutical carrier. Pharmaceutical preparations intended for systemic administration may be prepared by the addition of a polyene compound of formula

I as the active ingredient in a non-toxic, inert, solid or liquid carrier as commonly used in such preparations. The pharmaceutical preparations may be administered enterally or parenterally. Suitable pharmaceutical preparations for enteral administration are, for example, tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. The pharmaceutical compositions in the form of infusions or solutions for injection are suitable for parenteral administration.

The dosages in which the polyene compounds of formula I are administered vary depending on the route and form of administration and the requirements of the patient.

The polyene compounds of formula I can be administered in an amount of 5 to 200 mg daily in single or multiple doses. A preferred form of administration is capsules containing from about 10 mg to about 100 mg of the polyene compound.

The pharmaceutical preparations may contain an inert or other pharmacodynamically active component. The tablets or granules may contain a series of binders, excipients, carriers or diluents. Liquid preparations may for example be sterile, miscible solutions. In addition to the polyene compound of formula I, the capsules may contain an additional filler or sealant. Additives such as taste enhancers, preservatives, stabilizers, moisture retention or emulsifiers, salts of osmotic pressure, buffers and the like may also be used.

Said carriers and diluents may be organic or inorganic such as water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. A prerequisite is that all additives used in the manufacture of pharmaceutical preparations are non-toxic.

For external use, the polyene compounds of formula I are formulated as ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred forms. These pharmaceuticals for external use may be prepared by mixing the polyene compound as an active substance with a non-toxic, inert solid or liquid carrier suitable for external use, as commonly used in such preparations.

Suitable for external use are solutions containing from about 0.01 to about 0.3% (preferably 0.02 to 0.01%), as well as ointments and creams containing 0.05-5% (preferably 0.1 -2.0%) active substance.

Antioxidant such as tocopherol, N-methyl-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene may optionally be added to the pharmaceutical preparations.

The aryl group denoted by X in the triarylphosphonium group of formula-P (X) -Y- in the compounds of formula II or III includes all known aryl groups, especially mononuclear aryl groups such as phenyl, lower alkyl-substituted phenyl or lower alkoxy-substituted phenyl (for example tolyl, xylyl, mesityl and p-methoxyphenyl). Of the inorganic acid anions indicated by Y, the chlorine, bromine, iodine and hydrosulphate ion are preferred, and of the organic acids, the tosyloxy ion is preferred.

The alkoxy groups are denoted by Z in the dialkoxyphosphinyl groups of the formula:

-P / Z / j o

Lower alkoxy groups containing from 1 to 6 carbon atoms, in particular methoxy and ethoxy groups, are preferred.

Preferred electron-attracting groups are those that exhibit little of this property. Examples of aryl and aralkenyl groups which may be substituted by one or more electron-weakening electron-withdrawing substituents denoted by R ₂₀ in the sulfone group of the formula:

Oh

I in which R1 has the meanings indicated above are the phenyl and styryl groups which may be substituted at the ο-, m- or β-position by methoxy, phenoxy, acetoxy, dimethylamino, phenylmethylamino, acetylamino, thiomethylthiophenylthioacetyl , chlorine, bromine or cyano radical or in the m-position with the nitro group.

The starting compounds of formulas II and III are partially novel compounds.

A compound of formula II wherein m is O and A is a triarylphosphonium group have the following formula:

in which R _p R ₂ , R ₃ , R ₄ , R _p X and Y have the meanings given above.

The compounds of formula II in which m is O and A is a dialkoxyphosphinyl group have the following formula:

* 3 1 · ^ΡΙΖ1 1 ό 1 ο п-с s

wherein RpR ₂ , R ₃ , R ₄ , R _; u Zea same as above. The compounds of formula II-a and II-c can be prepared, for example, by treating the corresponding (R ^ Rj) substituted benzene with formaldehyde in the presence of hydrochloric acid (for example concentrated hydrochloric acid), if desired in a solvent (especially glacial acetic acid). acid) to give a compound of formula II wherein m is O and A is halogen, i. e. a compound of formula ΙΙ-i. The halide of formula I-1 is reacted with triaryl phosphine in a solvent, preferably triphenylphosphine in toluene or benzene, or with trialkylphosphite, in particular triethylphosphite.

In the presence of an alkoxy group in the aforementioned (R4-Rp-benzene ring, it can be introduced, for example, by alkylation of a hydroxyl group present. Thus, the corresponding phenol may be reacted, preferably, in a solvent (eg alkanol). and in the presence of a base (e.g. potassium carbonate), with an alkyl halide (e.g. methyl iodide) or with dimethyl sulfate.

A compound of formula II in which m is 1 and A is a triaryl phosphonium group has the formula:

Well,

I - I CH, P PQ * ν * nth

I * in which R _p R ₂ , R ₃ , R ₄ , R _s , X and Y are the same as above.

Compounds of formula II in which m is 1 and A is dialkoxyphosphinyl have the formula:

»>

in which Rp Rj, R ₃ , R ₄ , R _s and Zea are the same as above.

The compounds of formulas II-b and II-d can be prepared by initially formulating the corresponding (R ₍ -R _s ) -benzene. This can be accomplished, for example, by formulating (R ^ Rj) -substituted benzene in the presence of Levis acid As a formulating agent in this case can be used ester of formic acid, formyl chloride and dimethylformamide.Levis acids are particularly suitable for halides of zinc, aluminum, titanium, tin and iron such as zinc chloride, aluminum trichloride, trichloride, tin tetrachloride and ferric trichloride ka it and halides of inorganic and organic acids such as phosphorus oxychloride and methane sulfochloride.

If the formulating agent is in excess, the formulation can be carried out without the addition of another solvent. It is recommended that the formulation be carried out in an inert solvent (eg nitrobenzene or chlorinated hydrocarbon such as methylene chloride) at a temperature between 0 ° C and the boiling point of the mixture.

The (R? R? -Benzaldehyde obtained) can then be extended in the usual way by condensation with cold acetone (i.e. at a temperature of about 0-30 ° C) in the presence of an alkaline substance (e.g. dilute aqueous sodium hydroxide solution). base) to give (K ₁ -K ₅ ) -phenyl-but-3-en-2-one, which can be converted to the corresponding (R _t R ₃ ) -phenyl-3-methyl-3-hydroxy- penta-4-ene-1 yn in a known manner by an organometallic reaction (e.g., by a Grignard reaction with the addition of acetylene) The resulting tertiary ethylene carbinol may then be partially hydrated The conventional tertiary ethylene carbino can then be converted, by allyl rearrangement, to the desired phosphonium salt of formula II-b, in which m is 1, by exposure to triaryl phosphine, in particular triphenyl phosphine, in the presence of a halogen hydrogen such as hydrogen chloride or hydrogen bromide in a solvent (eg benzene). The tertiary ethylene carbine can be halogenated to give a compound of formula II in which m is 1 and A is halogen, i.e. compound of formula II-k. This halide of formula II-k can be reacted with trialkyl phosphite (eg triethyl phosphite) to give the corresponding phosphonate of formula II-d.

Compounds of formula II in which m is O and A is a sulfone group have the formula:

«A Ο

_Where R _f , R _Jt R ₃ , R ₄ , R _s and R ₁₀ have the meanings already indicated.

The compounds of formula II-e can be prepared by dissolving (Rj-R _s ) phenol or the corresponding halogenbenzene in a polar solvent such as alcohol (eg methanol, ethanol or isopropanol) or in tetrahydrofuran or dimethylformamide or in glacial acetic acid and as a solution , at room temperature, is treated with sulfonic acid of the formula:

Oh

II ° p ^g »one where Rjo is the same as above, or with an alkali metal salt.

Isolation of the sulfone can be accomplished by neutralizing the reaction mixture by the addition of aqueous sodium bicarbonate solution and extracting the sulfone with an organic solvent (for example ethyl acetate or ether).

The compounds of formula II, wherein n is 1 and A is a sulfone group, are of the formula:

And in which R ₍ , R ₂ , R ₃ , R ₄ , R ₃ and R _jo have the meanings given above.

The compounds of formula I-f can be prepared in an analogous manner by reacting (I- _{I 3} ) -phenyl-3-methylpent-2,4-dien-1-ol or sulfinic acid halide, as described below. above or with an alkali metal salt thereof.

Compounds of formula II in which m is 0 and A is oxo, i.e. a compound of formula ΙΙ-g can be prepared, for example, by formulating (Rj-Rj) -benzene in the manner described above. Thus, (Rj-R1) benzene directly (Rj-Rj) benzaldehyde is obtained.

Compounds of formula I wherein m is 1 and A is oxo, i.e. a compound of formula II-h can be prepared, for example, by subjecting (Rj-R ₃ ) -phenyl-but-3-en-2-one [described above in connection with the preparation of compounds of formula II-b] Vitig reaction with ethoxycarbinol-methylenetrifenylphosphorane or with diethylphosphonic acid ethyl ester. The (Rj-Rj) phenyl-3-methyl-pent-2,4-diene-1-acid acid ethyl ester obtained is then reduced cold with mixed metal hydride, in particular lithium aluminum hydride, in an organic solvent (e.g. diethyl ether or tetrahydrofuran) to give N-p-phenyl-3-methyl-penta-

2,4-dien-1-ol. This alcohol is then oxidized by exposure to an oxidizing agent, for example manganese dioxide in an organic solvent such as acetone or methylene chloride at a temperature between 0 ° C and the boiling point of the mixture to obtain the desired (R, -Rj) -phenyl- 3-methyl-pent-2,4diene-1-al of formula II-h.

The compounds of formula III are also partially novel.

Compounds of formula III in which η is 0 and B is a triarylphosphonium group (II-a) or a dialkoxyphosphinyl group (I-c) can be readily prepared by reacting an optionally esterified 3halogenmethylcrotonic acid or optionally esterified 3-halogenmethylcrythylaryl triethylaryltrilaryl triethyl phosphine in a solvent, preferably with triphenyl phosphine in toluene or benzene or with trialkyl phosphite, especially triethyl phosphite.

Compounds of formula III in which η is 1 and B is a triarylphosphonium group (III-b) or a dialkoxyphosphinyl group (III-d) can be prepared, for example, by reducing the formyl group of an aldehyde of formula IIIh in which η is 1 , in a hydroxymethyl group using a metal hydride, such as sodium borohydride, in alkanol (e.g. ethanol or isopropanol). The resulting alcohol can be halogenated using a conventional halogenating agent (eg phosphorus oxychloride) and the resulting 8-halogen-

3.7-Dimethyl-octa-2,4-triene-1-carboxylic acid (a halide of formula III in which η is 1 and B is halogen) or a derivative thereof may be reacted with either triarylphosphine in a solvent, preferably triphenylphosphine in toluene or benzene to obtain the desired phosphonium salt of formula ΙΙΙ-h, or with trialkylphosphite, especially triethylphosphite, to obtain the desired phosphonate of formula Ill-d.

Compounds of formula ΙΠ-e in which η is 0 and B is a sulfone group can be prepared, for example, by reaction of 4hydroxy-3-methyl-but-2-en-1-al or the corresponding acetate or bromide in polar a solvent (e.g. isopropanol or nbutanol) as described above with one of the sulfinic acids described previously or with their alkali metal salt.

Compounds of formula ΙΙΙ-f, in which η is 1 and B is a sulfone group, can be prepared in a manner analogous to that described above by reacting, for example, 8-hydroxy-

3.7-Dimethyl-octa-2,4,6-triene-1-acid or the corresponding acetate or bromide of this alcohol with sulfinic acid as described or with an alkali metal salt thereof.

Compounds of formula ΙΙΙ-g in which η is 0 and B is an oxo group can be prepared, for example, by the oxidative cleavage of an esterified tartaric acid, for example, using lead tetraacetate at room temperature in an organic solvent such as benzene. The resulting glyoxalic acid derivative is then condensed in a known manner, more conveniently in the presence of an amine, with propionaldehyde at elevated temperature (e.g., at a temperature between 60 ° C and 110 ° C) with water to give the desired derivative of 3 -formyl-crotonic acid.

Compounds of formula ΙΙΙ-h in which η is 1 and B is an oxo group can be prepared, for example, by reacting 4,4 dimethoxy-3-methyl-but-1-en-3-ol with cold phosgene, preferably at -10 ° to -20 ° C, in the presence of a tertiary amine such as pyridine and condensation of the resulting 2-formyl-4-chloro-but-2-ene under reaction conditions

Vitig with optionally esterified 3-formylcrotonic acid or optionally esterified or esterified 3-formylcrotone alcohol to obtain the desired aldehyde of formula III-b.

According to the method developed in the present invention, the following interactions are obtained:

phosphonium salts of formulas II-a or IIb are reacted with aldehydes of formulas III-h or ΙΙΙ-g or phosphonium salts of formulas III-a or III-b are reacted with aldehydes of formulas IIh or II-g or phosphonates of formulas II-c or II-d are reacted with aldehydes of formulas ΙΙΙ-h or ΠΙ-g or phosphonates of formulas III-c or Ill-d are reacted with aldehydes of formulas ΙΙ-h or ΙΙ-g or sulfones of formulas II-e or Il-f are reacted with halides of formulas III-k or ΙΙΙ-ϊ or sulfones of formula ΙΠ-e or III-f are reacted with halides of formulas II-k or Il-1.

According to the Wittig method, the reaction components interact with each other in the presence of an acid binder, for example in the presence of an alkali metal alcoholate, such as sodium methylate or in the presence of an optionally alkyl substituted alkylene oxide, preferably in the presence of ethylene oxide or 1,2 -butylene oxide, if desired, in the presence of a solvent, such as a chlorinated hydrocarbon such as methylene chloride or dimethylformamide) at a temperature between room temperature and the boiling point of the reaction mixture.

According to the Horner method, the reaction components are reacted with each other by means of a base, preferably in an inert organic solvent medium, for example, using sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane or with using alkali metal alcoholate in alkanol (eg sodium methylate in methanol) at a temperature between 0 ° C and the boiling point of the reaction mixture.

According to Julia's method, the reaction components interact with each other using a condensing agent for convenience in a polar solvent environment. Suitable solvents are, for example, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran and hexamethylphosphoric acid triamide, as well as alkanols such as methanol, isopropanol or tert, butanol. Examples of strong bases which are preferred as condensing agents are alkali metal carbonates (especially sodium carbonate), alkaline earth carbonates, alkali metal hydroxides (e.g. sodium base or potassium base), alkali metal alcoholates (sodium methylate, and especially kaliate acetate, and especially kaliate alcoholates, alkali metal hydrides (eg sodium hydride), alkyl magnesium halides (eg methyl magnesium bromide) and alkali metal amides (eg sodium amide). The reaction proceeds rapidly at low temperature, especially below the freezing point (for example, between -50 and -80 ° C).

In some cases, it is appropriate to carry out the reactions described above in place, i.e. without isolating the phosphonium salt, phosphonate or sulfone from the medium in which they are obtained.

A carboxylic acid of formula I can in a known way be converted to acid chloride (for example by action with thionyl chloride, preferably pyridine), which in turn can give amide upon treatment with ammonia and, when reacted with alkanol, turn into ester.

The carboxylic acid ester of formula I can be hydrolyzed by known means (for example by treatment with an alkaline substance, in particular an aqueous sodium hydroxide solution or potassium hydroxide solution) at a temperature between room temperature and the reflux point of the reaction mixture and then to be amidated by acid halide or as described below.

The carboxylic acid ester of formula I can be directly converted to the corresponding amide, for example by treatment with lithium amide. The interaction of lithium amide and ester is mainly carried out at room temperature.

The carboxylic acid or the carboxylic acid ester of formula I can be conveniently reduced to the corresponding alcohol of formula I. The reduction is preferably carried out using a metal hydride or an alkyl metal hydride in an inert solvent. Preferred mixed metal hydrides, such as lithium aluminum hydride or bis (methoxy-ethyleneoxy) sodium aluminum hydride, are preferred. Suitable solvents are ether, tetrahydrofuran or dioxane when using lithium aluminum hydride and ether, hexane, benzene or toluene when working with diisobutyl aluminum hydride or bis (methoxy-ethyleneoxy) -odium aluminum hydride.

An alcohol of formula I may be esterified with an alkyl halide (e.g. ethyl iodide), for example, in the presence of a base, preferably sodium hydride, in an organic solvent such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide or in the presence of an alkali metal alkanol metal alcohol temperature between 0 ° C and room temperature.

An alcohol of formula I may also be esterified by treatment with an alkanoyl halide or anhydride, in particular in the presence of a base (e.g. pyridine or triethylamine) at room temperature and that of the mixture.

The alcoholic ester may be saponified in a known manner, for example, by the method described above in connection with the hydrolysis of a carboxylic acid ester.

An alcohol of formula I or an ester thereof may be oxidized in a known manner to give an acid of formula I. The oxidation is preferably carried out with silver (1) oxide and an alkaline substance in water or in an organic solvent miscible with water at temperature between room and boiling point of mixture.

An amine of formula I forms organic and inorganic acid addition salts. Examples of such salts are those formed with hydrochloric acids (in particular hydrochloric or hydrobromic acid), with other inorganic acids (eg sulfuric acid) and with organic acids (eg benzoic, acetic, citric or lactic acid).

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

The compounds of formula I can be as cis / trans mixtures, which, if desired, can be separated into cis and trans components or isomerized to only trans compounds in known ways.

The following examples illustrate the invention without limitation. The ether used is diethyl ether in the examples. In the examples, concentrated hydrochloric acid means an aqueous solution containing about 37% by weight hydrochloric acid. The term 35% formaldehyde, which is found in the examples, means an aqueous solution containing 35% formaldehyde. The term "low boiling petroleum ether" as used in the examples means petroleum ether boiling at a certain temperature.

Sodium hydride (50-60%) used is sodium chloride 30 to 60% by weight suspended in mineral oil.

Examples of carrying out the invention. Example 1

228 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-pent-2,4-diene-1-triphenylphosphonium bromide was introduced into a nitrogen atmosphere in 910 ml of dimethylformamide and cooled at 5 ° -10 A suspension of sodium hydride (about 50 wt%) in mineral oil (17.5 g) was added over 20 min. The mixture was stirred for 1 hour at about 10 ° C and then 61.8 g of 3 formyl ester crotonic acid butyl ester was added dropwise at 5-8 ° C, heated for 2 hours at 65 ° C and poured into 8 l of ice water. 300 g of sodium chloride were added and extracted with a total of 18 l of hexane. The extract was washed five times with 1 liter of methanol / water (6: 4) each time and twice with 1.5 liters of water, dried over sodium sulfate and evaporated under reduced pressure to give a residue of 9- (4-Methoxy-2,3,6-trimethyl phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1ic acid butyl ester, m.p. 80 ° -81 ° C.

Example 2

125.8 g of 9- (4-methoxy- butyl ester-

2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-

2,4, 6,8-Tetraene-1-acid is added to

2000 ml of absolute ethanol and a solution of 125.8 g of potassium base in 195 ml of water is added. Under nitrogen, the mixture was heated to reflux for 30 min, then cooled, poured into 10 l of ice water, then added about 240 ml of concentrated hydrochloric acid (pH 2-4) and extracted with total of 9 liters of methylene chloride. The extract was washed with about 6 l of water until neutral, dried over calcium chloride and evaporated under reduced pressure. The residue was dissolved in 700 ml of hexane. The precipitated 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraen-1-acid was melted at 228 ° -230 ° C.

Example 3

500 g of 2,3,5-trimethylphenol are added in 1840 ml of ethanol and 184 ml of water and 240 g of potassium hydroxide is slowly added to it. The resulting clear solution was added dropwise at 0-5 ° C for 30-45 min626 g of methyl iodide. The reaction mixture was stirred for 2 hours at room temperature and then an additional 12 hours at reflux at 60 ° C. Add 5 liters of water and extract with a total of 6 liters of diethyl ether. The extract is washed first with 3 liters of aqueous sodium hydroxide solution and then 2 times with 1 liter of water for each wash, dried over sodium sulfate and evaporated under reduced pressure. The residue of 2,3,5-trimethylanisole, after rectification, was refluxed at 88 ° -90 ° C at 10 mm Hg.

To 87.1 g of dimethylformamide while stirring at 10 ° -20 ° C for 20-30 minutes 184 g of phosphorus oxychloride were added dropwise. At the end of the addition, the temperature was raised to 25 ° C. To the resulting mixture was added 150 g of 2,3,5-trimethylanisole for 20 minutes under cooling to 10 ° -20 ° C. The reaction mixture was slowly warmed to a maximum of 115 ° C, stirred for 6 hours at 100 ° C to complete the reaction, cooled and poured into 2 kg of ice and water at a ratio of 1: 1 by volume and after the addition of 1500 ml of benzene, is treated with 500 g of sodium acetate. The formed aqueous phase was separated after stirring for 1 hour and again extracted with 1000 ml of benzene. The combined benzene extracts were washed sequentially with 480 ml of 1.5 aqueous hydrochloric acid and 500 ml of water, dried over sodium sulfate and filtered over 20 g of decolorized carbon. The filtrate was evaporated under reduced pressure. The remaining 2,3,6 trimethyl-β-anisaldehyde, after recrystallization from hexane, melts at 65 ° -66 ° C.

260 g of 2,3,6-trimethyl-p-anisaldehyde were added to a mixture of 3500 ml of acetone and 1400 ml of water and treated with 730 ml of 10 wt.% Aqueous sodium hydroxide under stirring and temperature 0 ° -5 ° C for about 30 min. The mixture was stirred for 3 days at room temperature, after the pH was lowered to 4-5 by the addition of acetic acid, concentrated under reduced pressure. The concentrate was extracted with a total of 3000 ml of diethyl ether. The ether extract was first washed with 700 ml of 5% aqueous sodium hydroxide solution, then washed with 700 ml of water, dried over sodium sulfate and evaporated under reduced pressure. The remaining oily product was 4- (4-methoxy-2,3,6-trimethylphenyl) -but-3-en-2-one and, after rectification, boiled at 120-127 ° C / 0.05 mm Hg.

36.45 g of magnesium was corroded superficially by small amounts of iodine, added in 1000 ml of tetrahydrofuran, and 162.5 g of ethyl bromide were added dropwise under nitrogen for 45 minutes. The temperature is raised to 8-10 ° C. It may rise to 25 ° C at the end of the addition. The reaction mixture was stirred by again adding 5-10 ml of alkyl bromide until the magnesium was completely dissolved. The resulting Grignard solution was then added dropwise at 0 ° C to a saturated solution of acetylene / tetrahydrofuran prepared from 650 ml of tetrahydrofuran by gassing for 3 hours with acetylene at -10 ° C to -5 ° C. The reagent was stirred 1 hour at 0 ° C, then acetylene gas at 0 ° C was added dropwise over 30-45 min together with a solution of 218 g of 4- (4-methoxy-2,3,6-trimethylphenyl) -but-3 -en-2-one in 250 ml of tetrahydrofuran. The reaction mixture was stirred for 24 hours at 0 ° C and then for 12 hours at room temperature. Pour into 4.5 kg of ice and water at a ratio of 3.5: 1 v.h., adjust the pH to about 4 by adding 700 ml of 3N hydrochloric acid and extract with a total of 3 l of diethyl ether. The ether extracts were washed to neutral with a total of 2 liters of water, dried over sodium sulfate and filtered over 20 g of decolorizing carbon. The filtrate was evaporated under reduced pressure and the residue of 5- (4-methoxy-2,3,6-trimethyl-phenyl) -3-methyl-3-hydroxy-pent-4-en-1-yn, after rectification at 125-135 ° C. 0.04 mm Hg, melting at 58-60 ° C.

244 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-3-hydroxy-pent-4-en-1-yne are dissolved in 400 ml of hexane and after the addition of partially poisonous palladium catalyst, are hydrogenated at room temperature and normal pressure. The hydrogenation is terminated after about 40-60 minutes after absorption of the amount of hydrogen required to saturate the acetylene ethylene bond of 325 l. The hydrogenated solution is filtered. The filtrate was washed with 300 ml of ethyl acetate and evaporated under reduced pressure. The residue is 5- (4-methoxy-2,3,6 trimethyl-phenyl) -3-methyl-3-hydroxy-pent-

1,4-diene melts at 46-47 ° C.

246 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-3-hydroxy-pent-1,4-diene were dissolved in 2400 ml of benzene. The solution was treated with 343 g of triphenylphosphonium hydrobromide, stirred for 24 hours at 60 ° C, cooled and the benzene separated. The precipitate was treated 4 times with 500 ml of benzene each and after the benzene washes were separated, it was dissolved in 700 ml of methylene chloride. The solution was evaporated under reduced pressure. The residue of 5- (4-methoxy-2,3,6-trimethyl-phenyl) -3methyl-pent-2,4-dien-1-triphenylphosphonium bromide was dried in vacuo before being used further.

Example 4

1775 g of lead tetraacetate (90%) was added gradually over 30 min at 25-30 ° C to a solution of 1000 g of dibutyl ester of dibutyl ester in 3850 ml of benzene. The reaction mixture was then stirred for 1 hour at room temperature. The precipitate was filtered off and extracted with 500 ml of benzene. The benzene extract was evaporated under reduced pressure. The residue is mainly glyoxalic acid butyl ester and, after rectification, boils at 65 ° C / 12 mm Hg.

836 g of the glyoxalic acid butyl ester obtained are added to 376 g of propionaldehyde. 40.8 g of di-n-butylamine were added dropwise at 60 ° C to the mixture. However, the reaction temperature should not be higher than 106 ° C. The reaction mixture was then stirred for 2 hours at 116111 ° C, cooled and dissolved in ether. The diethyl ether extract was washed successively with 500 ml of 1N sulfuric acid, 700 ml of water, 1000 ml of 5% aqueous sodium bicarbonate solution and finally with 1000 ml of water. It is dried over sodium sulfate and evaporated under reduced pressure. The residue is 3-formyl-crotonic acid butyl ester which, after rectification, boils at 93-105 ⁰ C / 14 mm Hg; ²⁵ "!

Example 5

28.5 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-pent-2,4-diene-1-triphenylphosphonium bromide were added under a nitrogen atmosphere to 240 ml of isopropyl alcohol. After the addition of 0.12 g of butylated hydroxy toluene, the mixture was cooled to -35 ° C, and at this temperature and vigorous stirring for 5 min was added 7.50 g of 3formylcrotyl acetate. The reaction mixture is then mixed with 7.2 g of an aqueous 50 wt% potassium hydroxide solution and the temperature should not rise above 25 ° C. The mixture was stirred at -30 ° C for 1 hour and a mixture of 110 g of water, 90 g of ice and 90 ml of hexane was added to the mixture. The hexane layer was separated. The aqueous phase is shaken 5 times with 90 ml of hexane each. The combined hexane extracts were washed 5 times with 180 ml methanol / water at a ratio of 80:20 rpm. for each of the washes. The hexane phase was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 1-acetoxy-9- (4-methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8 tetraene is an oil and can be purified on silica gel and eluting with hexane / diethyl ether 80:20 rpm

Example 6 g of 2,3,6-trimethyl-benzyltriphenylphosphonium bromide and 28 g of 7-formyl-3-methyl-octa-2,4,6-triene-1-acid butyl ester were mixed with 280 ml of absolute ethanol. A solution of 2.72 g of sodium in 160 ml of absolute ethanol was added dropwise to the mixture at a temperature between 0 and 10 ° C and stirred for 48 hours at room temperature. Pour into 800 ml of water and extract with a total of 3000 ml of hexane. The hexane extracts were shaken three times each time with 1000 ml of methanol at 60:40 volume, then dried over sodium sulfate and evaporated under reduced pressure. The residue is an oil and is 9- (2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid butyl ester.

Example 7.

9- (2,3,6-Trimethylphenyl) -3,7-dimethyl-nona-2,4,6,8-tetra-1-yl acid butyl ester was placed in 100 ml of absolute ethanol and then added to the mixture. added a solution of 10 g of potassium hydroxide in 20 ml of water. The reaction mixture was heated under a nitrogen atmosphere. Initially, the cloudy mixture was clarified to form a solution and after 30 minutes boiling was cooled and poured into water and ice. The reaction solution was extracted after acidification with concentrated hydrochloric acid with methylene chloride. The extract was washed with water to neutral, dried over calcium chloride and evaporated under reduced pressure. The residue is 9 (2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid, which, after recrystallization from ethyl acetate, melts at 191-192 ° C.

Example 8.

To 300 g of pseudocumene were added dropwise 700 ml of concentrated sulfuric acid, with the temperature increasing to 40 ° C. The mixture was then cooled to 20 ° C, 450 g of bromine was added and stirred for 1 hour at room temperature. Then, 700 ml of water were added dropwise, raising the temperature to 50 ° C. The resulting precipitate was filtered off and dissolved in 3000 ml of hot water. The insoluble 3,5,6tribromo-1,2,4-trimethylbenzene is separated and discarded. The aqueous solution was slowly added to 1000 ml of 80% by weight. sulfuric acid, which is heated to 180 ° C and flushed with steam. Steam separates 1-bromo-2,3,6-trimethylbenzene, which boils at 86 ° C / 6 mm Hg.

250 g of 1-bromo-2,3,6-trimethylbenzene were dissolved in 400 ml of diethyl ether. The solution was added dropwise at 20-30 ° C under gentle cooling to a suspension of 66.5 g of magnesium (activated with iodine) and 200 ml of diethyl ether. A solution of 135 g of ethyl bromide in 250 ml of diethyl ether was added dropwise at 20-30 ° C and then refluxed for 3-4 hours. After the magnesium is completely dissolved, 385 g of orthoformic acid ethyl ester dissolved in 250 ml of absolute diethyl ether are added to the solution. The reaction mixture was refluxed for 5 hours, the diethyl ether was evaporated and poured onto ice. 1000 ml of 5 N hydrochloric acid are added and the mixture is heated to reflux for 30 minutes in carbon dioxide. The distillate obtained after distillation with water is extracted with methylene chloride. The methylene chloride phase was evaporated under reduced pressure. The residue of 2,3,6 trimethylbenzaldehyde was boiled at 70-72 ° C / 1.2 mm Hg.

129.6 g of 2,3,6-trimethylbenzaldehyde were dissolved in 300 ml of methanol and cooled to 0 ° C after the addition of 70 ml of water. The mixture was treated with portions of 18.25 g of sodium borohydride, stirred for 1 hour, then poured onto ice and extracted with diethyl ether. The ether extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue of 2,3,6-trimethylbenzyl alcohol is further treated as follows:

g 2,3,6-trimethylbenzyl alcohol was dissolved in 175 ml of low boiling petroleum ether. 51 g of phosphorus tribromide dissolved in 60 ml of low-boiling petroleum ether were added dropwise over 2 hours at -10 ° C. The reaction mixture was stirred for 12 hours at room temperature, poured onto ice and extracted with diethyl ether. The ether extract is washed first with ice-cooled, saturated aqueous sodium bicarbonate solution, then with saturated aqueous salt solution, dried over sodium sulfate and evaporated under reduced pressure. The rest of

2,3,6-trimethylbenzyl bromide was boiled after rectification at 75-80 ° C / 0.05 mm Hg.

73.3 g of 2,3,6-trimethylbenzyl bromide were dissolved in 170 ml of benzene. To the solution was added 90.0 g of triphenylphosphine, whereby the temperature was raised to 40 ° C. The mixture was stirred for 12 hours at room temperature. The precipitated 2,3,6-trimethylbenzyl-triphenylphosphonium bromide was melted after washing with low boiling petroleum ether and dried at 240-242 ° C.

Example 9.

To 2700 ml of liquid ammonia, after addition of a small amount of ferric (111) nitrate, are added in portions under stirring and cooling

169.5 g of potassium. After the original blue color has disappeared, ie. after about 30-45 min, a stream of acetylene gas at a rate of 3 l / min is passed until the dark color of the reaction mixture becomes lighter. The gas flow was then reduced to 2 l / min and a solution of 500 g of methylglyoxal-dimethylacetal in 425 ml of diethyl ether was added dropwise. Gas leakage continued for 1 hour while stirring. The reaction mixture was then treated in portions with 425 g of ammonium chloride, slowly warmed to 30 ° C for 12 hours by evaporation of ammonia and extracted with 1600 ml of diethyl ether. The ether extract was dried over sodium sulfate and evaporated under reduced pressure. The residue of 4,4 dimethoxy-3-methyl-but-1-yn-3-ol boils, after rectification, at 33 ° C / 0.03 mm Hg; n _o "-1.4480.

198 g of 4,4-dimethoxy-3-methyl-but-1-yn-ol were dissolved in 960 ml of high-boiling petroleum ether and after addition of 19.35% palladium catalyst and 19.3 g quinoline, hydrogenated at normal conditions. After absorbing 33.5 liters of hydrogen, the hydrogenation is complete. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue of 4,4-dimethoxy-3-methyl-but-1-en3-ol was boiled after rectification at 70-72®C / 18 mm Hg.

195 ml of phosgene was added to 1570 ml of tetrachloromethane at -10 ° C. After the addition of 213 g of pyridine, the solution was added dropwise at -10 ° to -20®C 327 g.

4,4-dimethoxy-3-methyl-but-1-en-3-ol. The reaction mixture was slowly warmed to 25 ° C with stirring and then stirred for another 3 hours at room temperature. Cool to 15 ° C and add 895 ml of water. The aqueous phase was separated and discarded. The organic phase was left in the cold for 12 hours and then treated with 448 ml of 5 wt.% Aqueous sulfuric acid, stirred for 5 hours, washed with water, dried over sodium sulfate and evaporated under reduced pressure. formyl-4-chloro-but2-ene boiled after rectification at 37-40 ° C /

1.8 mm Hg; πθ ²³ = 1.4895.

165.7 g of 2-formyl-4-chloro-but-2-ene were dissolved in 840 ml of benzene and 367 g of triphenylphosphine were added thereto. The reaction mixture was heated to reflux for 12 hours under nitrogen and cooled to 20 ° C. The precipitated 2-formyl-but-2-en-4-triphenylphosphonium chloride melts after washing with benzene and drying at 250-252 ° C.

212.6 g of 2-formyl-but-2-ene-4-triphenylphosphonium chloride and 95 g of 3-formyl crotonic acid butyl ester were added to 1,100 ml of butanol and treated at 5 ° C with a solution of 57 g of triethylamine in 60 ml of butanol. The reaction mixture was then stirred for 6 hours at 25 ° C. It is cooled and poured into water and extracted with hexane. The hexane phase was initially washed several times with methanol / water at a ratio of 6: 4 rpm, then with water, dried over sodium sulfate and filtered. The filtrate is isomerized for 12 hours with iodine shaking. Iodine is removed by the addition of sodium thiosulphate. The filtrate was washed again with water, dried and evaporated under reduced pressure. The residue is 7-formyl-3-methyl-octa-2,4,6-triene-1-acid butyl ester which, after rectification, boils at 102-105 ° C / 0.09 mm Hg.

Example 10.

In the method described in Example 6: 2,4,6triisopropyl-benzyl-triphenylphosphonium bromide is condensed with 7formyl-3-methyl-octa-2,4,6-triene-1-acid butyl ester to form butyl ester of 9 (2,4,6-triisopropyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraen-1-acid in the form of an oil which is hydrolyzed by the method of Example 7 to give 9- (2,4,6triisopropyl-phenyl) -3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid, m.p. 221 ° C.

Example 11.

136 g of 1,3,5-triisopropyl-benzene, 228 ml of acetic acid, 420 ml of concentrated hydrochloric acid and 55 g of formaldehyde (35%) were heated at 60 ° C. The reaction mixture was stirred at this temperature for initially 3 hours, then 21 g of formaldehyde (35%) was added and stirred again for 12 hours, then cooled to room temperature and extracted with benzene. The benzene extract was washed successively with water, saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated under reduced pressure. The residue of 2,4,6-triisopropylbenzyl boiled, after rectification, at 70 ° C / 0.05 mm Hg.

69.6 g of 2,4,6-triisopropyl-benzyl chloride were dissolved in 1000 ml of xylene. 79.5 g of triphenyl phosphine were added to the solution. The mixture was stirred for 18 hours at 125 ° C, then cooled. At 80 ° C, precipitation of 2,4,6-triisopropyl-benzyltriphenylphosphonium chloride begins to precipitate, which after melting and washing with benzene melts at 237-238 ° C.

Example 12.

By the method described in example 6:

pentamethyl-benzyl-triphenylphosphonium chloride is condensed with 7formyl-3-methyl-octa-2,4,6-triene-1-acid butyl ester to give 9 (pentamethyl-phenyl) -3,7 -dimethyl-non-2,4,6,8tetraen-1-acid in the form of an oil which is hydrolyzed by the method described in Example 7 to 9- (pentamethyl-phenyl) -3,7-dimethyl-non-2,4 , 6,8-tetraene-1-acid, m.p. Mp 228-229 ° C.

Example 13.

184.5 g of pentamethylbenzene, 193 ml of glacial acetic acid, 355 ml of concentrated hydrochloric acid and 44 g of formaldehyde (35%) were heated at 65 ° C. The reaction mixture was stirred at this temperature for initially 3 hours, then added further

18.1 g formaldehyde (35%) and stirred again for 3 hours. It was cooled to room temperature and extracted with benzene for 12 hours. The benzene extract was washed successively with water, dilute aqueous sodium hydroxide solution and water, dried over sodium sulfate and evaporated under reduced pressure. The residual pentamethyl-benzyl chloride, after recrystallization from hexane, melts at 80-81 ° C.

101.6 g of pentamethyl-benzyl chloride, 149 g of triphenyl-phosphine and 250 ml of toluene were stirred for 5 hours at 100 ° C. 259 ° C.

Example 14.

g of 3-chloro-2,4,6-trimethyl-benzyltriphenylphosphonium chloride and 10 g of 7-formyl-3-methyl-octa-2,4,6-triene acid are heated to boiling, after stirring, by adding 40 g of 1,2-butylene oxide. The 1,2-butylene oxide was slowly distilled off. The reaction mixture was stirred for 30 min at 8O-82 ° C, then cooled and extracted with hexane. The hexane extract was shaken 5 times with 50 ml of methanol / water at 70:30 rpm, then dried over sodium sulfate and evaporated under reduced pressure to give 9 (3-chloro- butyl ester). 2,4,6-trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraen-1-acid as a residue.

Example 15.

9- (3-Chloro-2,4,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-acid butyl ester was heated to reflux under nitrogen at 50 ml of a 5% potassium ethanol solution by weight. After boiling, the solution was clarified and after 30 min cooled, poured into water and acidified with acetic acid. The precipitated 9- (3-chloro-2,4,6-trimethylphenyl) -3,7-dimethyl-nono-2,4,6,8-tetraen-1 acid after melting from benzene melts at 208-209 ° C. .

Example 16.

119 g of chloromethylene, 11.9 g of paraformaldehyde and 5.95 g of anhydrous zinc chloride are heated to 60 ° C under hydrogen chloride, stirring, initially for 8 hours and after addition of an additional 11.9 g of paraformaldehyde. lasts another 8 hours. The reaction mixture was then poured onto ice and extracted with diethyl ether. The ether extract was washed successively with water, aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. The residue of 3-chloro-2,4,6-trimethylbenzyl chloride was refluxed at 138 ° C / 17 mm Hg after rectification.

71.25 g of 3-chloro-2,4,6-trimethyl-benzyl chloride, 92 g of triphenyl phosphine and 375 ml of absolute toluene were heated at 100 ° C for 12 hours. After cooling crystallizes 3-chloro-

2.4.6-trimethyl-benzyl-triphenylphosphonium chloride, m.p. 233-235 ° C.

Example 17.

By the method described in Example 14, 3-nitro-

2.4.6-Trimethyl-benzyl-triphenyl phosphonium chloride is condensed with 7formyl-3-methyl-hepta-2,4,6-triene-1-acid butyl ester to form 9 (3-nitro- butyl ester). 2,4,6-Trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid in the form of an oil which, by the method described in Example 15, is converted to 9- (3-Nitro-2,4,6trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid, m.p. 205-206 ° C.

Example 18

g of nitromesitylene, 2 g of p-formaldehyde and 1 g of zinc chloride (anhydrous) were heated to 60 ° C and stirred under hydrogen chloride for 16 hours. The reaction mixture was poured onto ice and extracted with diethyl ether. The ether extract was washed successively with water, saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. The residue of 3-nitro-2,4,6, trimethyl-benzyl chloride is in the form of oil n _D ^{22 =} 1, 5373, and is treated as follows:

11.6 g of 3-nitro-2,4,6-triphenyl-benzyl chloride, 14 g of triphenyl phosphine and 100 ml of absolute benzene were refluxed for 24 hours. After cooling, 3-nitro-2,4,6-trimethyl-benzyltriphenylphosphonium chloride, m.p. Mp 252-253 ° C.

Example 19.

By the method described in example 14; 4methoxy-2,3,5,6-tetramethyl-benzyltriphenylphosphonium chloride is condensed with 7-formyl-3-methyl-octyl butyl ester-

2,4,6-triene-1-acid to form 9- (4-methoxy-2,3,5,6 tetramethyl-phenyl) -3,7-dimethyl-non-2,4,6 butyl ester, 8-Tetraene-1-acid in the form of an oil, which is converted, as described in Example 15, into 9- (4-methoxy-2,3,5,6-tetramethyl-phenyl) -

3,7-Dimethyl-non-2,4,6,8-tetraen-1-acic acid, m.p. 230-233'C.

Example 20.

g of 2,365,6-tetramethylphenol was dissolved in 55.3 ml of methanol, 7.25 g of potassium base dissolved in 5.5 ml of water were added and then 18.8 g of methyl iodide was added dropwise at 0-5 ° C. The reaction mixture was initially stirred for 2 hours at room temperature and for 12 hours at 60 ° C. It is cooled, diluted with 150 ml water and extracted with 100 ml diethyl ether. The ether extract was washed sequentially with 3 N aqueous sodium hydroxide solution and water, dried over sodium sulfate and evaporated under reduced pressure. The residue of 2,3,5,6-tetramethylanisole, after purification by absorption on silica gel (eluent: methylene chloride), melts at 53-55 ° C.

g of 2,3,5,6-tetramethylanisole in 110 ml of anhydrous acetic acid were added to 203 ml of 37 wt.% aqueous hydrochloric acid and 21.6 g of 37% formaldehyde were added dropwise thereto. The reaction mixture was heated to 70 ° C with stirring for 3 hours and, after the addition of new 8.3 g of 37% formaldehyde, was stirred for another 3 hours at 70 ° C. The mixture was then cooled to room temperature and extracted with 500 ml of benzene. The benzene extract was separated. The aqueous phase is shaken with benzene. The combined benzene extracts were washed sequentially with water, saturated aqueous sodium carbonate solution and again with water, dried and evaporated under reduced pressure. The residue of 4-methoxy-

2,3,5,6-Tetramethyl-benzyl chloride, after recrystallization from ethyl acetate hexane in a ratio of 3. melts at 104-105 ° C.

g of 4-methoxy-2,3,5,6-tetramethylbenzyl chloride, 34.7 g of triphenyl phosphine and 153 g of toluene were heated at 100 ° C for 12 hours. After cooling, 4-methoxy-2,3,5,6 tetramethyl-benzyl-triphenylphosphonium chloride was precipitated, m.p. Mp 251-252 ° C.

Example 21.

9- (4-Methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1ic acid was dissolved in 1000 ml of acetone. After the addition of 128 g of methyl iodide and 128 g of potassium carbonate, the solution was stirred under nitrogen for 16 hours at 55-60 ° and then evaporated under reduced pressure. The residue was dissolved in 1300 ml of petroleum ether (bp 80-105 C). 9 (4-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-one acid methyl ester crystallizes at -20 ° C and melts at 9399 ° C.

Example 22

In the manner described in Example 21, 9- (4methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraen-1-acid and ethyl iodide were converted to 9 - (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-yl acid ethyl ester, m.p. 104105 ° C; 9- (4-Methoxy-2,3,6-trimethyl-phenyl) -

3,7-Dimethyl-non-2,4,6,8-tetraene-1-acid and isopropyl iodide are converted to 9- (4-methoxy-2,3,6 trimethyl-phenyl) -3,7- isopropyl ester. dimethyl-non-2,4,6,8tetraene-1-acid (oil).

Example 23.

28.6 g of 9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nono-2,4,6,8-tetraen-1ic acid were added to 300 ml of benzene and under nitrogen. atmosphere was added to 12 g of phosphorus trichloride. The benzene is then distilled off under reduced pressure. 9- (4-Methoxy-2,4,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-acid acid chloride was dissolved in 1200 ml of diethyl ether. The solution was added dropwise at -33 ° C to 500 ml of liquid ammonia and stirred for 3 hours. The reaction mixture was then diluted with 500 ml of diethyl ether and stirred, without cooling for another 12 hours, to evaporate the ammonia. The residue was dissolved in 10 l of methylene chloride. The solution was washed twice with 3 liters of water, dried over sodium sulfate and evaporated under reduced pressure. The residue from the amide of 9- (4-methoxy-

2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-

2,4,6,8-Tetraene-1-acid, after recrystallization from ethanol, melts at 207209 ° C.

Example 24

In the manner described in Example 23, the chloride of 9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1 acid and the ethylamine is converted in 9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nono-2,4,6,8-tetraen-1 acid acid ethylamide, m.p. 179-180 ° C; and the chloride of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraen-1-one acid and the diethylamine are converted to the 9- (4-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid, m.p. 105-106 ° C.

Example 25

Obtain a capsule filler of the following composition:

9- (4-Methoxy-2,3,6-trimethyl-phenyl) -

3,7-Dimethyl-non-2,4,6,8-tetraene-1-acid ethyl ester-0.1 g, mixture of waxes-

51.4 g, vegetable oil-103.0 g, trisodium salt of ethylenediaminetetraacetic acid 0.5 g, weight of each capsule 150 mg, content of active substance in one capsule-10 mg.

Example 26.

Preparation of ointment containing 0.3% active substance with the following composition in g: 9 (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene -1-acid 0.3, cetyl alcohol-2.7, lanolin-6.0, white petrolatum-15.0 and distilled water to 100.0.

Example 27

Preparation of a water-in-oil emulsion containing 0.3% active substance of the following composition in g: 9- (4-methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4-ethylamide, 6,8 tetra-tetra-1-acid, -0.3, magnesium stearate 2.0 and perhydroqualene 13.0.

Example 28.

Preparation of a solution containing 0.1% active substance of the following composition: 9- (4methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraen-1-o acid-0.1 g, dimethyl sulfoxide-70.0 g and water to 100 ml.

Example 29.

As described in Example 1, 9- (4-Allyloxy-2,3,6-trimethyl-phenyl) ethyl ester -

3,7-Dimethyl-non-2,4,6,8-tetraen-1-one acid is obtained from 5- (4-allyloxy-2,3,6 trimethyl-phenyl) -3-methyl-penta-2,4 -diene-1-triphenylphosphonium bromide by reaction with 3-formyl crotonic acid ethyl ester. This compound was converted to 9 (4-allyloxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid by m.p. 198-200 ° C, by the method described in Example 2.

The 5 (allyloxy-2,3,6-trimethyl-phenyl) -3-methylpenta-2,4-diene-1-triphenylphosphonium bromide used as starting material can be obtained by the method of Example 3. In this method 1,3, 5-Trimethylphenol is alkylated with allyl bromide to give 1,3,5-trimethyl-phenyl allyl ether (b. 76-80 ° C / 0.05 mm Hg) by formulating the resulting ether to give 4 allyloxy -2,3,6-trimethyl-benzaldehyde (b. 90102 ° C / 0.15 mm Hg, by condensation of the resulting aldehyde with acetone to give (4-allyloxy-2,3,6-trimethyl- phenyl) -but-3-en1-al, mp 135-138 ° C / 0.05 mm Hg; by reacting the resulting ketone with acetylene to give gave 5- (4-allyloxy-2,3,6-trimethylphenyl) -3-methyl-3-hydroxy-pent-4-en-1-yne by partially hydrogenating the resulting tertiary acetylene carbinol to give 5 (4- allyloxy-2,3,6-trimethyl-phenyl) -3-methyl-3-hydroxy-pent-1,4-diene and by reacting the obtained tertiary ethylene carbinol with triphenylphosphine hydrobromide.

5- (4-Allyloxy-2,3,6-trimethyl-phenyl) -3-methylpenta-2,4-diene-triphenylphosphonium bromide, m.p. 114-116 ° C.

Example 30.

In the method described in Example 14, 9- (2,4,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-butyl acid butyl ester is obtained from 2, 4,6-trimethyl-benzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-triene-1-acid butyl ester. This product was converted to 9- (2,4,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-oic acid, mp 214-215 ° C in the manner described in Example 15.

Used as a starting product

2.4.6-Trimethyl-benzyl-triphenyl-phosphonium chloride was prepared by the method described in Example 18 by halogenformylation of mesethylene to give 2,4,6-trimethyl-benzyl chloride (b. 112 ° C / 12 mm Hg) and the reaction of this compound with triphenylphosphine.

Example 31

According to the method described in Example 14, 9- (2,3,4,6-tetra-methylphenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acid butyl ester is obtained from 2,3,4,6-Tetramethylbenzyltriphenylphosphonium chloride by reaction with 7-formyl 3-methyl-octa-2,4,6-triene-1-acid butyl ester. From this product, according to the method of Example 15, 9- (2,3,4,6-tetramethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-acid acid is obtained with m .t. 201-202 ° C.

Used as a starting product

2.3.4.6- Methyl l-benzyl-triphenylphosphonium chloride tetra is prepared by the method described in Example 16 by halogenformylation of 1,2,3,5-tetramethyl-benzene to give

2.3.4.6- Tetramethylbenzyl chloride (n _D 1, 5571) and reaction of this compound with triphenylphosphine.

Example 32

By the method described in Example 14, 9- (4-methoxy-2,6-dimethyl-phenyl) butyl ester -

3,7-Dimethyl-non-2,4,6,8-tetraen-1-one acid is obtained from 4-methoxy-2,6-dimethylbenzyl-triphenylphosphonium chloride by reaction with 7formyl-3-methyl-octa-2 butyl , 4,6-triene-1-acid. From this product, according to the method of Example 15, 9- (4-methoxy-2,6-dimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-triene-1-acid was obtained, m.p. . 207-208 ° C.

The 4methoxy-2,6-dimethyl-benzyl-triphenylphosphonium chloride used as starting material was prepared according to the method of Example 16 by halogenformylation of 3,5 dimethylanisyl to give 4-methoxy-2,6-dimethyl-benzyl chloride (n _D ² ° 1. , 5475) and the interaction of this compound with triphenylphosphine.

Example 33.

In the method described in Example 14, the 9- (3-methoxy-2,4,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-butyl acid butyl ester is obtained from 3methoxy-2,4,6-trimethyl-benzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methylacta-2,4,6-triene-1-acid butyl ester. This product was converted to 9- (3-methoxy-2,4,6-trimethyl phenyl) -3,7-dimethyl-non-2,4,6,8-tetraic acid, mp 196-198 ° C using the method described in Example 15.

The 3methoxy-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride used as starting material was prepared by the method described in Example 16 by halogenformylation of 2,4,6-trimethylanisole to afford 3-methoxy-2,4,6- trimethyl-benzyl chloride (n _D ² '-l, 5415) and reaction of this compound with triphenylphosphone 3-methoxy-

2,4,6-trimethyl-benzyl-triphenylphosphonium chloride and melting at 308-310 ° C.

Example 34

In the method described in Example 14, 9- (4-Methoxy-3-allyl-2,6-dimethyl-phenyl) -3,7-dimethyl-non-2,4-8,8-tetraen-1-butyl ester was butyl is prepared from 4methoxy-3-allyl-2,6-dimethyl-benzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methylacta-2,4,6-triene-1-acid butyl ester. This product, by the method of Example 15, was converted to 9- (4-methoxy-3-allyl-2,6-dimethyl-phenyl) -

3,7-Dimethyl-non-2,4,6,8-tetraene-1-acid, m.p. 160-161 ° C.

The 4methoxy-3-allyl-2,6-dimethyl-benzyl-triphenylphosphonium chloride used as starting material was prepared by the method described in Example 16 by halogenformylation of 3,5-dimethyl-2-alylanisole to yield

4-methoxy-3-allyl-2,6-dimethyl-benzyl chloride (n _with ² M, 5690) and reaction of the latter with triphenylphosphine.

Example 35

In the method described in Example 14, 9- (4-Methoxy-3-nitro-2,6-dimethyl-phenyl) -3,7-dimethyl-non-2,4-8,8-tetraen-1-yl acid ethyl ester was obtained. prepared from 4methoxy-3-nitro-2,6-dimethyl-benzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methylacta-2,4,6-triene-1-acid ethyl ester. In the method of Example 15, this compound was converted to 9 (4-methoxy-3-nitro-2,6-dimethyl-phenyl) 3,7-dimethyl-2,4,6,8-tetraene-1-acid by m. t. 109-110 ° C.

The 4methoxy-3-nitro-2,6-dimethyl-benzyltriphenylphosphonium chloride used as starting material was prepared as described in Example 16 by halogenformylation of 2-nitro-3,5-dimethylanisole to give 4-methoxy-3- nitro-2,6-dimethyl-benzyl chloride, m.p. 109-110 ° C and the reaction of this compound with triphenylphosphine. 4-Methoxy-3-nitro-2,6-dimethyl-benzyl-triphenylphosphonium chloride melts at 230-232 ° C.

Example 36

In the method described in Example 14, 9- (4-ethoxy-2,3,6-trimethyl-phenyl) ethyl ester -

3,7-Dimethyl-non-2,4,6,8-tetraene-1-acid (mp. 96-97 ° C) is obtained from 4-ethoxy-

2,3,6-Trimethyl-benzyl-triphenylphosphonium chloride by reaction with ethyl ester of

7-Formyl-3-methyl-octa-2,4,6-triene-1-acic acid.

The ethoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride used as starting material was prepared by the method described in Example 18 by alkylation of 2,3,5-trimethylphenol to give 2,3,5-trimethylphenol ethyl ester with mp 93-95 (R) by halogenformylation of the resulting ether to give 4-ethoxy-2,3,6-trimethyl-benzyl chloride (mp. 63-64 ° C) and by reaction of the latter with triphenylphosphine.

Example 37

In the method described in Example 14, 9- (4-isopropoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-butyl butyl ester is obtained from 4isopropoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6triene-1-acid butyl ester. This product, by the method of Example 15, is converted to 9- (4-isopropoxy-

2.3.6-trimethylphenyl) -3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid, m.p. 176-177 ° C.

The 4isopropoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride used as starting material was prepared by the method of Example 18 by alkylation of 2,3,5-trimethylphenol to give 2,3,5-trimethylphenyl isopropyl ether (m. 115 ° C / 11 mm Hg), by halogenformylation of the obtained ether to give 4-isopropoxy-2,3,6-trimethyl-benzyl chloride (n _D ²⁰ = 1,55433) and by reaction of the latter with triphenylphosphine .

Example 38

According to the method described in Example 14, 9- (3-dimethylamino-2,4,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid ethyl ester (light yellow oil) is obtained from 3-dimethylamino-2,4,6-trimethylbenzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-triene-1-acid ethyl ester.

The 3-dimethylamino-2,4,6-trimethyl-benzyltriphenylphosphonium chloride used as starting material was prepared by the method described in Example 16 by halogenformylation of N, N-dimethylmesidine to give 3-dimethylamino-2,4,6- trimethylbenzyl chloride (b. 71 ° C / 11 mm Hg) and reaction of this compound with triphenylphosphine.

Example 39.

1.7 g of 8-diethoxyphosphono-3,7-dimethyl-octa-2,4,6-triene-1-acid acid ethyl ester were added to 8.0 ml of tetrahydrofuran. The solution was cooled to 0 ° C after 0.27 g of sodium hydride (50-60%) was added. The mixture was stirred at 0 ° C for 30 min and then a solution of 0.96 g of 2,3,6-trimethyl-p-anisaldehyde in 3 ml of THF was added dropwise over 15 min. The reaction mixture was stirred for 7 hours at room temperature, poured onto ice and extracted with diethyl ether after the addition of 2 N hydrochloric acid. The ether extracts were washed to neutral with water, dried over sodium sulfate and evaporated under reduced pressure. 9- (4-Methoxy- ethyl ester of ethyl ester)

2.3.6-trimethyl-phenyl) -3,7-dimethyl-non-

2,4,6,8-Tetraene-1-acid is melted at 104105 ° C.

Instead of the sodium chloride (0.27 g) used above, alkali metal alcoholate can also be used as a condensing agent, for example sodium ethylate (0.125 g sodium in 5 ml ethanol).

Example 40

3.03 g of 8-bromo-3,7 dimethyl-octa-2,4-triene-1-acid acid ester is heated with 1.66 g of triethylphosphite slowly to 125 ° C. The excess bromine ester is distilled. The residue was cooled and poured onto ice. It is extracted with diethyl ether and aqueous sodium bicarbonate solution, dried and evaporated under reduced pressure. The residue, consisting of ethyl ester of 8-diethoxyphosphono-3,7-dimethyl-octa

2.4.6-Triene-1-acid, is reacted immediately with 2,3,6-trimethyl-β-anisaldehyde as described above.

Example 41

1- (Phenyl-sulfonyl) -methyl-4-methoxy-2,3,6-trimethyl-benzene was dissolved in 10 ml of tetrahydrofuran. The solution was cooled to -78 ° C, 0.51 g of butyllithium was added and then a solution of 8-bromo-3,7-dimethyl-octa-2,4,6-triene-1-acid acid ethyl ester (1,8

d) in 8 ml of tetrahydrofuran. The reaction mixture was stirred for 2 hours at -78 ° C, two hours at -40 ° C and 16 hours at t ° from 0 ° to + 5 ° C. The mixture was poured onto ice and extracted with ether after 2N hydrochloric acid was added. The diethyl ether extracts were washed to neutral with water, dried over sodium sulfate and evaporated under reduced pressure. 9- (4-Methoxy- ethyl ester of ethyl ester)

2.3.6- Trimethyl-phenyl) -9- (phenyl-sulfonyl) -

3,7-Dimethyl-non-2,4,6-triene-1-acid (2.8 g) was diluted with 8 ml of absolute ethanol. The solution was treated at 0 ° C in two portions with

1.2 g of powdered sodium ethylate. The mixture was stirred at 0 ° C for 30 min, then at 80 ° C for 2 h, then cooled. It is poured onto ice and after the addition of 2N hydrochloric acid is extracted with diethyl ether. The ether extract was washed to neutral with water, dried over sodium sulfate and evaporated under reduced pressure. The residue of 9- (4-methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid ethyl ester was melted at 105 ° C.

Example 42.

16.8 g of 4-methoxy-2,3,6-trimethyl-benzyl alcohol, 17.4 g of benzenesulfonic acid sodium salt, 20.0 ml of isopropanol and 30.0 ml of glacial acetic acid were heated at reflux for 16 hours. fridge in a nitrogen atmosphere. The reaction mixture was cooled and 200 ml of water was added in portions, neutralized by the addition of sodium bicarbonate. The organic layer was separated, washed several times with aqueous sodium bicarbonate solution (5% by weight), dried over sodium sulfate and evaporated under reduced pressure. The residue is 1- (phenylsulfonyl) -methyl-4-methoxy-2,3,6-trimethylbenzene and shows the following IR spectrum: 1592, 1580, 1302, 1149, 118 cm ¹ .

Example 43

1.08 g of 4-methoxy-2,3,6-trimethylbenzyl chloride, 1.67 g of 8- (phenylsulfonyl) -3,7-dimethyl-octa-2,4,6-triene-1-acid acid ester and 10 ml of dimethylformamide were cooled to 0 ° C and 0.374 g of solid sodium ethanolate was added. The reaction mixture was stirred at room temperature for 30 min, poured onto ice and extracted with diethyl ether after the addition of 2N hydrochloric acid. The ether extract was washed to neutral, dried over sodium sulfate and evaporated under reduced pressure. 9- (4-Methoxy-2,3,6 trimethyl-phenyl) -8- (phenyl-sulfonyl) -3,7-dimethyl-non-2,4-triene-1-acid acid ethyl ester ( as described in Example 42), to form benzylsulfonic acid as a by-product and additional carbon-carbon double bond in the title compound, is transformed into the desired ethyl ester of 9 (4-methoxy-2,3,6'-trimethyl-phenyl) -3,7 dimethyl-non-2,4,6,8-tetraene-1-acic acid (mp 104-105 ° C).

Example 44

8.5 g of 8-bromo-3,7 dimethyl-octa-2,4,6-triene-1-acid acid ester were dissolved in 95 ml of dimethyl sulfoxide. To the solution, in a nitrogen atmosphere, 0.45 g of the benzene sulfonic acid sodium salt are added in the cold. The mixture was stirred for 1 hour at room temperature, then poured onto ice and extracted with diethyl ether. The ether extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue of 8- (phenyl-sulfonyl) -3,7-dimethyl-octa-2,4,6-triene-1-acid acid ethyl ester melts at 114-115 ⁰ C.

Example 45

By the method of Example 21, 9- (4-Methoxy-2,3,5,6-tetramethyl-phenyl) ethyl ester -

3,7-Dimethyl-non-2,4,6,8-tetraen-1-acid (mp 105-106 ° C) is obtained from 9- (4methoxy-2,3,5,6-tetramethyl) -phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-one acid and ethyl iodide;

9- (4-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraen-1-acid (bright yellow oil) 2-diethylaminoethyl ester is obtained from 9 - (4-methoxy-

2.3.6-trimethyl-phenyl) -3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid and diethylaminoethyl chloride; and (3- (4-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid (3-pyridyl) methyl ester (m.p. 113114 ° C) was prepared from 9- (4-methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid and beta-picoline chloride.

Example 46

9- (4-Methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-nono-2,4,6,8-tetraen-1ic acid was dissolved in 200 ml of tetrahydrofuran. 5.5 ml of phosphorus trichloride were added and the solution was stirred at room temperature for 2 hours. It is cooled to 0 ° C and then 50 ml of pyridine are added first and then 50 ml of propargyl alcohol is added dropwise at t ° 0-5 ° C. The mixture was stirred for 2 hours at room temperature and diluted with water. The organic phase was washed successively with water, dilute hydrochloric acid and 2% aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. 9- (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-2,4,6,8-tetraic acid propargyl ester is obtained, which melts at 94-95 ° C. after absorption on alumina and the use of benzene as eluent.

Example 47

By the method of Example 46, 9- (4-Methoxy-2,3,6-trimethyl-phenyl) -3,7 dimethyl-non-2,4,6,8-tetraen-1-acid allyl ester (m mp. 66-68 ° C) is obtained from 9- (4-methoxy-

2.3.6-trimethyl-phenyl) 3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid and allyl alcohol.

Example 48

According to the method of Example 23, 9- (4-Methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-acid acid ethylamide (m mp 201-201 ° C) is obtained from the chloride of 9 (4-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1 9-(4-methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid acid morpholide is obtained from the chloride of 9- (4-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid and morpholine.

Example 49

9- (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7 dimethyl-non-2,4,6,8-tetra-1-acid acid ethyl ester (50:50 mixture of cis and trans) chromatographed on 1.5 kg of aluminum oxide (activity grade 1) using hexane / diethyl ether in a ratio of 80:20 rpm as eluent. 9- (4-Methoxy-2,3,6-trimethyl-phenyl) - ethyl ester is isolated

3,7-Dimethyl-non-2-trans, 4-dis, 6-trans, 8-trans-tetra-1-acid as a light yellow oil.

Example 50

The 4-methoxy-2,3,5-trimethyl-benzyltriphenyl-phosphonium chloride used as starting material in Example 51 was prepared in a manner analogous to that described in Example 8, in the following sequence:

2.3.6- Trimethyl phenol

2.3.6- trimethylanisole

4-methoxy-2,3,5-trimethyl-benzyl chloride. Example 51

Analogous to the method of Example 6:

4-Methoxy-2,6-dimethyl-3-ethyl-benzyltriphenyl-phosphonium chloride was condensed with 7-formyl-3-methyl-octa-2,4,6triene-1-acid ethyl ester to give ethyl 9- (4-Methoxy-2,6-dimethyl-3-ethylphenyl) -3,7-dimethyl-nona-2,4,6,8-tetra-1-acid acid ester, which according to the method of Example 7 is converted to 9- (4-Methoxy-2,6-dimethyl-3-ethylphenyl) -3,7-dimethyl-nono-2,4,6,8-tetraen-1ic acid, mp 197-198 ° C.

Example 52

The 2-methoxy-2,6-dimethyl-3-ethyl-benzyltriphenylphosphonium chloride used as the starting compound in Example 53 can be prepared by a method analogous to that described in Example 8, in the following sequence:

3,5-dimethylphenol

-acetoxy-3,5-dimethyl-benzene

2-acetyl-3,5-dimethyl-phenol 2-ethyl-3,5-dimethyl phenol 2-ethyl-3,5-dimethyl-anisole 4-methoxy-2,6-dimethyl-3-ethylbenzyl chloride.

Example 53

Similar to the method described in example 6:

4-Methoxy-3,5-diethyl-2,6-dimethylbenzyl-triphenylphosphonium chloride was condensed with 7-formyl-3-methyl-octa-2,4,6-triene-1-acid ethyl ester to give ethyl 9- (4-Methoxy-3,5-diethyl-2,6-dimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetra-1-acid ester, which according to the method of Example 7 converted to 9- (4methoxy-3,5-diethyl-2,6-dimethyl-phenyl) acid, m.p. Mp 153-154 ° C.

Example 54.

4-Methoxy-3,5-diethyl-2,6-dimethylbenzyl-triphenylphosphonium chloride used as the starting compound in Example 55 can be prepared by a method analogous to that described in Example 8 by the following sequence

3.5-dimethyl-phenol

-acetoxy-3,5-dimethyl-benzene

2-acetyl-3,5-dimethyl-phenol 2-ethyl-3,5-dimethyl-phenol 1-acetoxy-2-ethyl-3,5-dimethyl-benzene

6-acetyl-2-ethyl-3,5-dimethyl-phenol

2,6-Diethyl-3,5-dimethyl-phenol

2,6-Diethyl-3,5-dimethyl-anisole 4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl chloride.

Example 55.

Analogous to the method described in Example 6: 4-Propoxy-2,3,6-trimethyl-benzyltriphenyl-phosphonium chloride was condensed with 7-formyl-3-methyl-octa-2,4,6triene-1-acid ethyl ester. to obtain 9- (4-propoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1ic acid ethyl ester, which is converted by the method of Example 7 in 9- (4-propoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1ic acid, mp 200-201 ° C .

Example 56.

4-Propoxy-2,3,6-trimethyl-benzyltriphenylphosphonium chloride used as starting material can be prepared in a manner analogous to that described in Example 8, that is, in the following sequence:

2.3.5-trimethylphenol

2.3.5-Trimethyl-propoxy-benzene 4-propoxy-2,3,6-trimethyl-benzyl chloride

Example 57

Analogously to the method described in Example 6, 4-ethoxy-2,3,6-trimethyl-benzyltriphenyl-phosphonium chloride was condensed with 7-formyl-3-methyl-octa-2,4,6-triene-1-acid ethyl ester. to give 9- (4-Ethoxy-2,3,6-trimethyl-phenyl) ethyl ester -

3,7-Dimethyl-non-2,4,6,8-tetraic acid, which is converted to 9- (4-ethoxy-

2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-

2,4,6,8-tetraene-1-acid, mp 219-220®C, by the method of Example 7.

Example 58.

In the method described in Example 6, 3,5-dichloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride was condensed with 7-formyl-3-methyl-octa-2,4,6-triene-1-acid ethyl ester. to obtain 9 (3,5-dichloro-2,4,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid ethyl ester, which the method of Example 7 was converted to 9 (3,5-dichloro-2,4,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid with m.p. Mp. 220-222 ° C.

Example 59

Similar to the method described in Example 6, 3-chloro-2,4,6-trimethyl-benzyl-triphenyl-phosphonium chloride was condensed with 7-formyl-3-methyl-octa-2,4,6-triene-1- ethyl ester This acid to afford 9- (3-chloro-2,4,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraic acid ethyl ester, mp 84 -85 ° C.

Example 60.

The 3-chloro-2,4,6-tri methyl-benzyl-triphenylphosphonium chloride used as a starting product can be prepared by a method analogous to that described in Example 8, that is, in the following sequence:

2.4.6- Trimethyl-aniline

2.4.6- Trimethyl-chl orbenzene

3-chloro-2,4,6-trimethyl-benzyl chloride.

Example 61

36.5 g of 1-ethoxycarbonyl-2,6-dimethylhepta-1,3,5-triene-7-triphenylphosphonium bromide were dissolved in 200 ml of dimethylformamide.

15.0 g of 4-methoxy-3-butyl-2,6-dimethyl-benzaldehyde were added and at 10 ° C, a solution obtained from 1.64 g of sodium in 40 ml of absolute ethanol was added dropwise. The mixture was then stirred for 12 hours at room temperature, 500 ml of methanol / water were added at 60:40 rpm. and extracted with hexane. The hexane extract was washed with methanol / water at 60:40 rpm, then washed with water, dried over sodium sulfate and evaporated. 9- (4-Methoxy-3-butyl-2,6-dimethyl-phenyl) - ethyl ester is obtained

3,7-Dimethyl-non-2,4,6,8-tetraene-1-acid, which, by the method of Example 7, is converted to 9- (4-methoxy-3-butyl-2,6-dimethylphenyl) -3,7-Dimethyl-non-2,4,6,8-tetraene-1 acid, m.p. 147-148®C.

Example 62

To 294 ml of butyric acid anhydride was added 2 ml of a concentrated aqueous solution of sulfuric acid and at room temperature 122 g of 3,5 dimethylphenol were added. The temperature was raised to 40 ° C and then raised to 80 ° C. The mixture was stirred for 1 hour and then diluted with 60 ml water and 60 ml ethanol, poured into ice water and extracted twice with 500 ml hexane for each extraction. The hexane extract was washed with water and with aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. 1-Butyryloxy-3,5-dimethyl-benzene is obtained, which is refluxed at 123-125 ° C / 11 mm Hg after rectification.

To 180 g of 1-butyryloxy-3,5-dimethylbenzene at room temperature were added 340 g of aluminum chloride. The mixture was stirred for 4 hours at 90-95 ° C, then cooled to 70 ° C, poured onto ice and 3N aqueous hydrochloric acid and extracted with ether. The ether extract was washed with water until neutral, dried over sodium sulfate and evaporated. 2-Butyryl-3,5-dimethylphenol is obtained which melts at 48-52 ° C after recrystallization from petroleum ether.

2-Butyryl-3,5-dimethyl-phenol was dissolved in 100 ml of glacial acetic acid. After the addition of 3 drops of perchloric acid, the solution was hydrogenated under normal conditions in the presence of 0.5 g of platinum oxide. After absorbing 3.0 liters of hydrogen, the hydrogenation is stopped. The catalyst was filtered off and the filtrate was extracted with ether.

The ether extract was washed with water to neutral, dried over sodium sulfate and evaporated. 2-Butyl-3,5-dimethylphenol is obtained, which melts at 65-67 ° C after absorption on silica gel using methylene chloride / hexane in a ratio of 1: 1 by volume as eluent.

83.0 g of 2-butyl-3,5-dimethyl-phenol were dissolved in 225 ml of methanol. After the addition of 60 g of potassium hydroxide in 25 ml of water, 34.2 g of methyl iodide at room temperature are added to the solution. The mixture was heated to reflux for 3 hours, then cooled, diluted with water and extracted with ether. The ether extract was washed with dilute sodium hydroxide solution, dried over sodium sulfate and evaporated. 2-Butyl-3,5-dimethylanisole is obtained, which is purified by absorption on silica gel, using hexane / methylene chloride in a ratio of 70:30 rpm. as eluent before further use.

5.5 ml of phosphorus oxychloride was added dropwise with stirring to 4.6 ml of dimethylformamide. The temperature was raised to 30 ° C. To the mixture was added dropwise 9.6 g of 2-butyl-3,5-dimethylanisole, poured into ice water after 30 to 35% aqueous sodium acetate was added thereto, stirred for 1 hour and stirred. extracted with benzene. The benzene extract was washed with water, dried over sodium sulfate and evaporated. 4-Methoxy-3-butyl-2,6-dimethyl-benzaldehyde is obtained, which is purified by absorption on silica gel using hexane / methylene chloride at a ratio of 1: 1 v.h. as eluent before condensing with 1ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5triene-7-triphenylphosphonium bromide.

Example 63

7-Formyl-3-methyl-octo-2,4,6-triene-1-acid ethyl ester was dissolved in 600 ml of absolute ethanol. 1.8 g of sodium borohydride were added dropwise. The mixture was stirred at 10 ° C for 2 hours and then poured into ice water and 3 H aqueous hydrochloric acid. Extract with ether. The ether extract was washed successively with water, saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. 8 Hydroxy-3,7-dimethyl-octa-2,4,6-triene-1-acid acid ethyl ester is obtained, which is further processed as follows:

8.5-Hydroxy-3,7-dimethyl-octa-2,4,6-triene-1-acid acid was dissolved in 380 ml of ether. The solution was cooled to 0 ° C and after the addition of 3 drops of pyridine 28.6 g of phosphorus tribromide in 120 ml of hexane were added dropwise. The mixture was stirred at 0 ° C for 20 minutes and poured into ice water. It is extracted with ether and the ether extract is washed successively with water, saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. 8-Bromo-ethyl ester is obtained

3,7-Dimethyl-octa-2,4,6-triene-1-acid, which is further treated as follows:

43.7 g of 8-bromo-3,7 dimethyl-octa-2,4,6-triene-1-acid acid ester was dissolved in 500 ml of benzene and 42.0 g of triphenylphosphine were added. The mixture was stirred for 12 hours at room temperature, then cooled to 0 ° C. The precipitated 1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-triene-7-triphenylphosphonium bromide melts at 193-194 ° C.

Example 64.

Analogous to the method described in Example 61: 3,4-dimethoxy-2,6-dimethyl-benzaldehyde condensed with 1-ethoxycarbonyl-2,6-dimethylhepta-1,3,5-triene-7-triphenylphosphonium bromide to give 9 (3,4-Dimethoxy-2,6-dimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-acid acid ethyl ester, which according to the method of Example 7 is converted to 9 (3,4-dimethoxy-dimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid, mp 203204 ° C.

Example 65

The 3,4-dimethoxy-2,6-dimethyl-benzaldehyde used as starting material can be prepared in a manner analogous to that described in Example 64, in the following sequence:

2.4-dimethyl phenol

2.4-dimethyl-6-nitro-phenol

2.4-dimethyl-6-nitro-anisole

2.4-dimethyl-6-amino-anisole

2.4-dimethyl-6-hydroxy-anisole

2.4-dimethylveratrol

Example 66.

Analogous to the method described in Example 48: 9- (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid chloride is reacted with methylamine, to give 9 (4-Methoxy-2,3,6-trimethyl-1-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid acid methylamide, mp.206 ° C.

9- (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid chloride is reacted with isopropylamine to give 9- (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid, mp 200 ° C.

9- (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid chloride is reacted with butylamine to give 9 ( 4-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid, m.p. 178 ° C.

9- (4-Methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetra-1-acid acid chloride is reacted with hexylamine to give 9- (4-Methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid, m.p. Mp 157-158 ° C.

Example 67.

9- (4-methoxy-2,3,6-trimethylphenyl) -

3,7-dimethyl-2,4,6,8-non-tetraen-1-ol

In a 5 liter round bottom flask fitted with a stirrer, a low temperature thermometer, an inlet tube for dry nitrogen and an outlet tube, a drip funnel connected to a bubbler filled with mineral oil, place 150 g (0.436 mol) of ethyl ester on 9 - (4-Methoxy-2,3,6 trimethylphenyl) -3,7-dimethyl-2,4,6,8natetraic acid and 800 ml of toluene. The contents were stirred until complete dissolution of the solid phase. Using a dry ice bath, the initial temperature was lowered to -60 ° C and 780 ml of a 25% solution of diisobutylaluminum hydride (DIBAL) in toluene (1.155 mol) was added dropwise. The initial yellow coloration of the solution or suspension with the addition of DIBAL darkens and finally the reaction mixture is a clear, slightly viscous, dark orange-red solution. After stirring for one hour, the cooling was reduced and the internal temperature allowed to rise to -40 ° C. At this temperature, a 50% aqueous solution of methanol is added dropwise under gentle cooling, so that after completion of the drop, the temperature is approximately 10 ° C. At this point 140 ml of saturated sodium sulfate solution are added dropwise, allowing the temperature to gradually rise to 25 ° C. At the end of the addition, aluminum hydroxide begins to precipitate with the formation of heat. After stirring for several minutes, 800 ml of chloroform was added to the slurry and the slurry was stirred for 10 minutes. The precipitate was removed by filtration through a 12-inch Buchner funnel and washed three times with 500 ml of chloroform each. The combined filtrates were washed sequentially with 600 ml of water, with 600 ml of water containing 10 ml of 3N hydrochloric acid, with 600 ml of saturated aqueous sodium bicarbonate solution and with 600 ml of water and then dried over sodium sulfate. Distillation of the solvent on a rotary evaporator yields 130-145 g of crystalline residue. To it was added 1 l of hexane and stirred vigorously until complete dispersion of the precipitate. The product retained on the walls is scraped. The yellow crystalline precipitate was obtained by filtration, washed with enough hexane to coat the precipitate on the funnel, then dried under vacuum first 12-15 mm (created by a water pump), then at 0.5 mm to constant weight. The yield of the product is 119-123 g, m.p. 127.5-129.5 ° C.

Distillation of the hexane from the filtrate and washings of the rotary evaporator yields a residue of 12-15 g which crystallizes very slowly and yields about 6-8 g of a very high quality product.

Example 68

9- (4-Methoxy-2,3,6-trimethylphenyl) -3,7 dimethyl-2,4,6,8-non-tetraen-1-ol

156 g (0, 0 g) were placed in a 5 liter round-bottom flask with nitrogen gas and equipped with a stirrer, thermometer, gas inlet and outlet pipe, connected to a bubbler filled with mineral oil and a six inch long Gooch tube. 5 mol) 9- (4-methoxy-2,3,6 trimethyl-phenyl) -3,7-dimethyl-2,4,6-nonatetraen-1-ol, 564 g (4 mol) methyl iodide and 2.5 l tetrahydrofuran . To the solution, stirring, at a temperature of 20-25 ° C for a period of about 1 hour, is added slowly 24 g (1.0 mol) of sodium hydride from a 500 ml Erlenmeyer flask connected through a Gooch tube. The yellowish solution becomes cloudy and turns brownish in color. For about 5 to 5 minutes the temperature rises to 28 ° C but is maintained at 25 ° C after external cooling. After 2.5 hours, the reaction vessel was cooled to 10 ° C by an ice bath, and the excess sodium hydride was decomposed by the addition of 10 drops of 50% aqueous methanol. The solvent was distilled off on a rotary evaporator, leaving a partially crystalline residue, which was dissolved in 500 ml of benzene and transferred to a separatory funnel where 15 were washed sequentially with three 500 ml portions of saturated sodium bicarbonate solution and once with water. containing little sodium sulfate. To the benzene solution was added 100 mg of 20 butylated hydroxy toluene (BHT), together with anhydrous sodium sulfate, then the solvent was distilled off on a rotary evaporator, the residue being an orange syrup (172 g). 25

This syrup, along with other 167 g, similarly obtained, was dissolved in 750 ml of warm hexane and filtered. The solution was stirred and allowed to crystallize at room temperature for about 1 hour and then at 0 ° C for further crystallization. All this is done in a nitrogen atmosphere. The orange-yellow crystalline product was separated by filtration (under nitrogen) and washed twice with hexane. 35 After drying, first at 10-15 mm and then at 0.5 mm to constant weight, 266 g (81%) of product are obtained, which melts at 67,569.5 ° C.

Example 69. 40

9- (4-Methoxy-2,3,6 trimethyl phenyl) -3,7-dimethyl-2,4,6,8 nonatetraen-1-ol butyl ester. In nitrogen medium, 6.0 g of 9 (4-methoxy -2,3,6-dimethyl-phenyl) -3,7 dimethyl-nonatetraen-1-ol, (0.0192 mol), 45 are dissolved in 150 ml of tetrahydrofuran, containing 28.05 g of n-butyl iodide. All were placed in a 250 ml round-bottom flask fitted with a stirrer, thermometer, a tube for introducing nitrogen, and an opening for placing 50 solids through which 0.92 g of sodium hydride was added. The mixture was stirred for 48 hours, then cooled, and the excess hydride was decomposed by careful addition of methanol. The mixture was then diluted with 500 ml of water and extracted three times with 50 ml of ether. After drying over magnesium sulfate, the solvent was distilled off with a rotary evaporator and the residue was dissolved in 10 ml of hexane. After the addition of 10 ml of methanol, 2.5 g of crystals of the starting material, mp 107-112 ° C, were separated. After removal of the solid, the filtrate was removed from the solvent and the residue was chromatographed on 200 g of silica gel. From the fraction eluted with 50% ether in hexane, 2.6 g of a solid are obtained which, after recrystallization from methanol, gives 1.5 g of dark yellow crystals, mp.5254 ° C.

Claims (30)

1. A compound of formula: wherein Rj and Rj are lower alkyl, R ₃ is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, nitro, amino, lower alkylamino, lower alkanoylamino or a heterocyclic radical, R ₄ is lower alkoxy, R ₃ is alkyl, , lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, amino, lower alkanoylamino, lower alkylamino or N-heterocyclic group and R ₆ is alkanoyloxymethylene, alkenyloxycarbinol, alkynyloxycarbinol, monoalkyl carbamoylcarbamoylcarbamoyl -carbamoyl, N-heterocyclylcarbonyl or alkoxycarbonyl, wherein the alkoxy moiety is unsubstituted substituted or substituted with alkylamino, morpholino, piperidyl, pyridyl, alkyl substituted piperidyl or alkyl pyridyl, or pharmaceutically acceptable salts thereof. 2. A compound of formula: wherein R _t and R 1 are lower alkyl, R ₃ is hydrogen or lower alkyl; R ₄ is lower alkoxy; R _s is hydrogen, lower alkyl or lower alkoxy and R ₆ is alkoxycarbonyl or carbamoyl, or pharmaceutically acceptable salts thereof. The compound of claim 1, wherein R ₆ is alkoxycarbonyl. The compound of claim 3, wherein the compound is 9 (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid methyl ester . The compound of claim 3, wherein the compound is ethyl 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-one acid. The compound of claim 3, wherein the compound is 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2-trans, 4-cis, 6-trans, 8-trans-tetraene ethyl ester -1 acid. The compound of claim 3, wherein the compound is 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,4,8-tetraen-1-isopropyl ester acid. The compound of claim 3, wherein the compound is 9 (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid butyl ester . The compound of claim 3, wherein the alkoxy group of the alkoxycarbonyl radical is substituted with an alkylamino, morpholino, piperidyl, pyridyl, alkylsubstituted piperidyl or alkylsubstituted pyridyl moiety. The compound of claim 9, wherein the compound is diethylaminoethyl ester of 9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1ic acid. The compound of claim 9, wherein the compound is (3- (pyridyl) methyl ester of 9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-non-2,4,6,8- tetraene-1 acid. The compound of claim 1, wherein R ₆ is alkynyloxycarbonyl. The compound of claim 12, wherein the compound is allyl ester of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene-1-acid. The compound of claim 1, wherein R ₆ is alkynyloxycarbonyl. The compound of claim 14, wherein the compound is the propargyl ester of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-o acid. The compound of claim 1, wherein R is alkanoyloxymethylene. Fr. The compound of claim 16, wherein the compound is 1-acetoxy-9- (4methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraene. The compound of claim 1, wherein R ₆ is carbamoyl. The compound of claim 18, wherein the compound is an amide of 9- (4-methoxy- 2,3,6-trimethyl-phenyl) -3,7-dimethyl-non- 2,4,6,8-tetraene-1-acid. The compound of claim 1, wherein R ₆ is mono or lower alkylcarbamoyl. The compound of claim 20, wherein the compound is 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid acid ethylamide. The compound of claim 21, wherein the compound is 9- (4methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid ethylamide . The compound of claim 20, wherein the compound is 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-non-2,4,6,8-tetraen-1-acid acid diethylamide. The compound of claim 1, wherein R ₄ is N-heterocyclylcarbonyl. The compound of claim 24, wherein the compound is 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethylnona-2,4,6,8-tetraene-1-acid acid morpholide. The compound of claim 1, 5 wherein R ₅ is lower alkenyl. The compound of claim 1, wherein at least one of R ₃ and R ₃ is a nitro group and R ₆ is alkoxycarbonyl. The compound of claim 27, 10 wherein the compound is 9 (4-methoxy-3-nitro-2,6-dimethyl-phenyl) 3,7-dimethyl-non-2,4,6,8-tetraene-ethyl ester. 1's acid. The compound of claim 1, wherein at least one of R ₃ and R ₁ is lower alkylamino and R ₆ is alkoxycarbonyl. The compound of claim 1, wherein at least one of R ₃ or R ₅ is a lower alkenyloxy radical. Publication of the Patent Office of the Republic of Bulgaria Sofia - 1113, Γ Blvd. M. Dimitrov 52-B