CH624373A5 - Process for the preparation of polyene compounds - Google Patents

Description

The present invention relates to a process for the preparation of new polyene compounds of the general form

in the Ri, R2 and R3 lower alkyl, R4 lower alkoxy, Rä and Rs methyl or trifluoromethyl, R9 formyl, hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxycarbonyl, lower alkenoxycarbonyl, lower alkynoxycarbonyl, carbamoyl, mono (lower alkyl) carbamoyl , mean the alkyl) carbamoyl or N-heterocyclylcarbonyl, and R5, R7, R10, Rh, Ri2 and RJ3 denote hydrogen or fluorine; with the restriction that at least one of the radicals R5, R7, R10, Ru, Ri2 and R13 are fluorine or at least one of the radicals R6 and R8 are trifluoromethyl, and pharmaceutically acceptable salts of these compounds.

The polyene compounds of the formula I can be obtained as cis / trans mixtures which, if desired, can be separated into the ice and trans components or isomerized to the all trans compounds in a manner known per se.

The above-mentioned lower alkyl groups mainly contain up to 6 carbon atoms, such as the methyl, ethyl, propyl, isopropyl or 2-methylpropyl group. The lower alkoxy groups also primarily contain up to 6 carbon atoms, such as the methoxy, ethoxy or isopropoxy group.

The above-mentioned alkoxymethyl and alkoxycarbonyl groups can contain both unbranched and branched alkoxy groups having up to 20 carbon atoms, such as the methoxy, ethoxy, isopropoxy or cetyloxy group. Of these, however, alkoxy groups having up to 6 carbon atoms are preferred.

The alkenoxy and alkynoxycarbonyl groups also primarily contain alkenoxy and alkynoxy radicals with up to

6 carbon atoms, such as the allyloxy or propargyloxy radical.

The alkanoyloxymethyl groups are primarily derived from lower aikanecarboxylic acids having 1 to 6 carbon atoms, e.g. B. of acetic, propionic or pivalic acid, but optionally also of higher aikanecarboxylic acids

7 to 20 carbon atoms, e.g. B. from the palmitic or stearic acid.

The carbamoyl group can be replaced by straight-chain or branched lower alkyl radicals, e.g. B. by methyl, ethyl or

30th

35

40

45

50

55

60

Isopropyl, mono- or di-substituted, such as. B. the methyl carbamoyl, dimethyl carbamoyl or diethyl carbamoyl group.

The N-heterocyclyl radicals of the N-heterocyclylcarbonyl groups are primarily 5- or 6-membered heterocyclic radicals which optionally contain, in addition to the nitrogen atom, oxygen, nitrogen or sulfur as a further heteroatom. Examples of this are the piperidino, morpholino, thiomorpholino or pyrrolidino radical.

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

Representative representatives of the new polyene compounds are:

9- (4-methoxy-2,3,6-trimethylphenyl) -2- £ luor-3,7-dimethyl-

2 (Z), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester, 9- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3,7-dimethyl- 2nd

(Z), 4 (E), 6 (Z), 8 (E) -nonatetraenoic acid ethyl ester, 9- (4-methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl-2

(E), 4 (E), 6 (Z), 8 (E) -nonatetraenoic acid methyl ester, 9- (4-methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl -2 (Z), 4 (E), 6 (Z), 8 (E) -nonatetraenoic acid methyl ester,

9- (4-methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl-2

(E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid methyl ester, 9- (4-methoxy-2,3,6-trimethylphenyl) -4-fluoro-3,7-dimethyl-2

(E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester, 9- (4-methoxy-2,3,6-trimethylphenyl) -4-fluoro-3,7-dimethyl-2

(E), 4 (Z), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester, 9- (4-methoxy-3,4,6-trimethylphenyl) -3-methyl-7-trifluoromethyl-2 (E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid methyl ester,

9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-5 -

fluor-2,4,6,8-nonatetraenoic acid ethyl ester, 9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-8-

fluoro-2,4,6,8-nonatetraenoic acid methyl ester, 9- (4-methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-7-

ethyl methyl-2,4,6,8-nonatetraenoate, 9- (4-methoxy-2,3,6-trimethylphenyl) -8-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (E), 8 (Z) -nonatetraenoic acid methyl ester,

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9- (4-Methoxy-2,4,6-trimethylphenyl) -3-trifluoromethyl-7-methyl-2 (E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester.

The new polyene compounds of the formula I are pharmacodynamically valuable compounds. They can be used for topical and systemic therapy of benign and malignant neoplasms, of premalignant lesions and also for systemic and topical prophylaxis of the affection mentioned.

The new polyene compounds of formula I are relatively non-toxic. The tumor-inhibiting effect of the process products is significant. In the papilloma test, tumors induced with dimethylbenzanthracene and croton oil regress. The following table provides information on this.

Table I

connection

Vitamin A-

Administered

Decrease of from example:

Hypervitaminosis *

dose

Papillomas

Effective dose mg / kg / wk in diameter

mg / kg / day

%

1

12.5

50

-37

2nd

100

400

-65

3A

50

200

-79

100

-60

50

-35

25th

-24

3B

200

-28

4th

> 200

400

-20

5A

> 200

400

-51

5B, 7

75

400

-82

100

-61

25th

-41

6

> 200

400

-25

8th

> 200

400

-34

* Bollag: Europ. J. Cancer Vol. 10 (1974) 732-733.

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

The preparations used for systemic use can, for. B. be prepared by adding a compound of formula I as an active ingredient non-toxic, inert solid or liquid carriers which are conventional in such preparations.

The agents can be administered enterally or parenterally. For enteral application z. B. Agents in the form of tablets, capsules, dragées, syrups, suspensions, solutions and suppositories. Agents in the form of infusion or injection solutions are suitable for parenteral administration.

The dosages in which the process products are administered can vary depending on the type of application and route of use and on the needs of the patients.

The process products can be administered in amounts of 25 to 100 mg daily in one or more doses.

The preparations can contain inert or pharmacodynamically active additives. Tablets or granules e.g. B. can contain a number of binders, fillers, carriers or diluents. Liquid preparations can, for example, be in the form of a sterile, water-miscible solution. In addition to the active ingredient, capsules can also contain a filler or thickener. Furthermore, taste-improving additives, as well as the substances usually used as preservatives, stabilizers, moisturizers or emulsifiers, as well as salts for changing the osmotic pressure, buffers and other additives can also be present.

The above-mentioned carriers and diluents can be made from organic or inorganic substances, e.g. B. from water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. consist. The prerequisite is that all auxiliary substances used in the manufacture of the preparations are non-toxic.

For topical use, the process products are expediently in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. used. Ointments and creams and solutions are preferred. These preparations intended for topical use can be prepared by admixing the process products as an effective component of non-toxic, inert, solid or liquid carriers which are customary in such preparations and are suitable for topical treatment.

The preparations can optionally contain an antioxidant, e.g. B. tocopherol, N-methyl-y-tocopheramine and butylated hydroxyanisole or butylated hydroxytoluene.

The process according to the invention for the preparation of the new polyene compounds of the formula I is characterized in that a compound of the general formula

13

with a compound of the general formula

14

12th

B

R

R

11

10th

implements, or that a connection of the general formula

IIb with a compound of the general formula

5

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65

5

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implements, or that a connection of the general formula

HC

13

12

11

with a compound of the general formula

B

implements

where in the formulas IIa, IIb, Ile and lilac, Illb, IIIc one of the radicals A and B is the oxo group, and the other radical is either a triarylphosphonium group of the formula _P [Y] © 3Z®, in which Y aryl and Z is the anion of a inorganic or organic acid, or a dialkoxyphosphinyl group of the formula —P [X] 2, in which X is alkoxy, is Dar-I

O

poses; Rj, Rj, R3, R4, R5, Rg, R7, Rg, Rio, R11, R12 and Rj3 have the meaning given for formula I; R14 represents alkoxymethyl, dialkoxymethyl, alkanoyloxymethyl, alkoxycarbonyl, alkenoxycarbonyl or alkynoxycarbonyl when B represents the oxo group; and R14 means formyl, hydroxymethyl, alkoxymethyl, dialkoxymethyl, carboxyl, alkoxycarbonyl, alkenoxycarbonyl or alinoxycarbonyl when B represents a triarylphosphonium or dialkoxyphosphinyl group and hydrolyzes an acetal obtained.

The aryl groups denoted by Y in the triarylphosphonium methyl group of the formula -P [Y] 3®Z® generally include all known aryl radicals, but in particular mononuclear radicals such as phenyl or lower alkyl- or lower alkoxy-substituted phenyl, such as tolyl, xylyl, Mesityl and p-methoxyphenyl.

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

The alkoxy radicals denoted by X in the dialkoxyphosphinylmethyl group of the formula -P [X] 2 are predominantly

O

lower alkoxy radicals with 1-6 carbon atoms, especially methoxy and ethoxy.

Some of the compounds of formula II are new. They can be prepared, for example, by reacting an appropriately substituted benzene in a known manner with a formylating agent in the presence of a Lewis acid. The resulting 4- (subst. Phenyl) but-3-en-2-one (IIa) is thereby converted in a known manner to ethyl 3-methyl-5 with (diethoxy-phosphinyl) -acetic acid ethyl ester or with (diethoxyphos-phinyl) -fluoroacetic acid ethyl ester - (Subst. phenyl) -penta-2,4-diene-l-acidic acid ester or converted to 2-fluoro-3-methyl-5- (subst. phenyl) -penta-2,4-diene-l-acidic acid ethyl ester.

The carboxylic acid ester obtained in each case is then known in a known manner with the aid of diisobutylaluminium hydride or with bis- (2-methoxyethoxy) sodium aluminum hydride to give 3-methyl-5- (subst. Phenyl) -penta-2,4-dien-l-ol or reduced to 2-fluoro-3-methyl-5- (subst. phenyl) -penta-2,4-dien-l-ol and by treatment with an oxidizing agent,

e.g. B. with manganese dioxide in an organic solvent, such as acetone or methylene chloride, converted into the starting compound of formula IIb, in which A represents the oxo group.

Starting compounds of the formula IIb in which A represents a triarylphosphonium group or a dialkoxyphosphinyl group can be obtained by 3-methyl-5- (subst. Phenyl) -penta-2,4-dien-l-ol or 2 -Fluoro-3-methyl-5- (subst. Phenyl) -penta-2,4-dien-l-ol in a known manner, for example treated with a phosphorus trihalide or phosphorus pentahalide and the halide obtained in each case with a triarylphosphine or a trialkyl converts phosphite.

Starting compounds of formula IIa with a trifhior-methyl group in the side chain can, for. B. can be obtained by using an appropriately substituted benzaldehyde with a propargyl Grignard reagent, e.g. B. with a compound of formula F3C-C = C-MgBr and the resulting propargyl derivative in an acidic medium by the action of mercury sulfate is subjected to a Meyer-Schuster rearrangement.

Starting compounds of the formula IIb are also accessible by reacting a compound of the formula IIIb with a compound of the formula

IV

where Rj, R2, R3, R4, R5 and A have the meaning given above,

implements.

If A is the oxo group in the compound of the formula IV, the compound of the formula IV can form a compound of the formula with a compound of the formula IIIb in which B represents either a triarylphosphonium group or a dialkoxyphosphinyl group

R

3rd

11

10th

R

"4

where Rj, R2, R3, R4, Rs, R8, Rio, Ru and R14 have the meaning given above, the restriction given for the formula I being removed because these new intermediates are not necessarily substituted in the side chain by fluorine or trifluoromethyl have to.

If B in the compound of the formula IIIb is the oxo group, the reaction is carried out with a compound of the formula IV in which A represents a triarylphosphonium group or dialkoxyphosphinyl group.

The compounds of the formula IIIb are known from the literature.

The compounds of formulas IIa, IIb and Ile are combined with the compounds of formulas lilac, Illb and IIIc

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6

the conditions of the Wittig or Horner reaction to the compounds of formula 1 implemented.

According to the procedure given by Wittig, the components are in the presence of an acid-binding agent, e.g. B. in the presence of an alkali metal alcoholate, such as sodium methylate, or in the presence of an optionally alkyl-substituted alkylene oxide, in particular in the presence of ethylene oxide or 1,2-butylene oxide, optionally in a solvent, for. B. in a chlorinated hydrocarbon, such as methylene chloride, or also in dimethylformamide, in a temperature range from room temperature to the boiling point of the reaction mixture.

According to the procedure given by Horner, the components are prepared using a base and preferably in the presence of an inert organic solvent, e.g. B. with the aid of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or also with the aid of an alkali metal alcoholate in an alkanol, for. B. with the help of sodium methylate in methanol, in a temperature range between 0 ° and the boiling point of the reaction mixture.

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

A carboxylic acid ester of the formula I can be prepared in a manner known per se, e.g. B. by treatment with alkalis, in particular by treatment with aqueous alcoholic sodium or potassium hydroxide solution, hydrolyzed in a temperature range between room temperature and the boiling point of the reaction mixture and either directly amidated via an acid halide or, as described below.

A carboxylic acid ester of formula I can e.g. can be converted directly into the corresponding amide by treatment with lithium amide. The lithium amide is advantageously reacted with the ester in question at room temperature.

A carboxylic acid or a carboxylic acid ester of the formula I can be reduced to the corresponding alcohol of the formula I in a manner known per se. The reduction is advantageously carried out using a metal hydride or alkyl metal hydride in an inert solvent. Mixed metal hydrides such as lithium aluminum hydride or bis- [methoxy-ethoxy] sodium aluminum hydride have proven to be particularly suitable as hydrides. Can be used as solvents u. a. Ether, tetrahydrofuran or dioxane when using lithium aluminum hydride; and ether, hexane, benzene or toluene if diisobutylaluminum hydride or bis- [methoxyethoxy] sodium aluminum hydride are used.

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

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

An alcohol ester can be prepared in a manner known per se, e.g. B.

as described above for the saponification of the carboxylic acid esters.

An acetal obtained can be obtained in a known manner by treatment with a proton donor in an inert solvent, e.g. B. by treatment with hydrochloric acid in tetrahydro furant hydrolyze.

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

A carboxylic acid of the formula I obtained, as mentioned initially, forms salts with bases, in particular with the alkali metal hydroxides, preferably with sodium and potassium hydroxide.

example 1

9- (4-Methoxy-2,3,6-trimethylphenyl) -2-fluoro-3,7-dimethyl-2 (Z), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester 5 , 05 g of 4- (diethoxyphosphinyl) -2 (Z, E) -fluoro-3-methyl-crotonic acid ethyl ester in 10 ml of 1,2-dimethoxyethane are in the cold at 0-5 ° C in a suspension of 0.83 g of sodium hydride (50% oil dispersion) added dropwise in 50 ml of 1,2-dimethoxyethane. The reaction mixture is stirred at 23 ° C. for one hour. The resulting dark brown suspension is then mixed with 4.35 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (E), 4 (E) -pentadien-l-al in 20 ml 1,2-dimethoxyethane was added, the mixture was stirred under argon at 23 ° C. for two hours, then acidified to pH 4 by adding 1N hydrochloric acid and extracted with methylene chloride (3 × 200 ml). The combined extracts are washed with water and with a saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure. The remaining 9- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3,7-dimethyl-2 (Z), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid- ethyl ester is purified by adsorption on 250 g of silica gel [eluent: ether / petroleum ether (5:95)]. The pure crystalline compound melts at 140-143 ° C.

Example 2

9- (4-Methoxy-2,3,6-trimethylphenyl) -2-fluoro-3,7-dimethyl-2 (Z), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester

5.52 g of 4-diethoxyphosphinyl) -2 (Z, E) -fluoro-3-methyl-crotonic acid ethyl ester in 10 ml of 1,2-dimethoxyethane are added to a suspension of 0.984 g of sodium hydride (50 % Oil dispersion) added dropwise in 50 ml of 1,2-dimethoxyethane. The mixture obtained is stirred at 23 ° C. for one hour. The resulting dark brown suspension is then treated with 4.80 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z), 4 (E) -pentadien-l-al in 20 ml 1 , 2-Dimeth-oxyethane added. The mixture obtained is stirred under argon at 23 ° C. for two hours, then introduced into 250 ml of ice water and worked up as described in Example 1. The resulting oily 9- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3,7-dimethyl-2 (Z), 4 (E), 6 (Z), 8 (E) -nonatetraen ethyl acetate is purified by adsorption on 200 g of silica gel [eluent: ether / petroleum ether (5:95)]. After recrystallization five times from petroleum ether, the ester melts at 103-113 ° C. According to analysis by high pressure liquid chromatography, the product is approximately 90% pure.

The 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2- (E), 4 (E) -pentadien-l-al used as the starting material in Example 1 and the 5- (4th -Methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z), 4 (E) -pentadien-l-aI, used as starting material in Example 2, z. B. are produced as follows

5

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624 373

a) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl

2 (Z, E), 4 (E) -pentadienic acid methyl ester 4.92 g sodium hydride (50% oil dispersion) are mixed with 330 ml 1,2-dimethoxyethane (distilled over lithium aluminum hydride). 20.08 g (dimethoxvphosphinyl) -acetic acid methyl ester are added dropwise to the mixture at 0 ° C. The mixture is warmed to 23 ° C. and stirred at this temperature for two hours under argon. 20.0 g of 4- (4-methoxy-2,3,6-trimethylphenyl) -3-buten-2-one are then added dropwise in 50 ml of 1,2-dimethoxyethane. The resulting thick white paste is stirred at 23 ° C. for 45 minutes, then heated under reflux conditions for 2.5 hours, then cooled in an ice bath and added in portions to 1.211 ice water. The resulting solution is neutralized by adding 2N salic acid (pH 6-7) and then extracted with methylene chloride (3 x 100 ml). The combined methylene chloride extracts are washed with water (3 x 200 ml) and with a saline solution (1 x 300 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z, E), 4 (E) -pentadienoic acid methyl ester is purified by adsorption on 250 g of silica gel [eluent: chloroform] . The ester is a light orange colored oil and consists of the isomeric mixture of Z and E isomers in a ratio of 2: 3.

b) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-

2 (Z, E), 4 (E) -pentadien-l-ol 40.0 g 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z, E), 4 ( E) -pentadienic acid methyl ester are dissolved in 50 ml of dry ether. 106 ml of diisobutylaluminum hydride are added to the solution at -73 ° C. under argon. The reaction mixture is stirred at -730 C for 0.5 hours. The course of the reaction is monitored by thin layer chromatography. After adding another 100 ml of diisobutylaluminum hydride in three portions within 30 minutes at -73 ° C, thin layer chromatography shows that only traces of the starting material are still present. The reaction mixture is then gradually warmed up to -30 ° C. and 250 ml of methanol-water (1: 1) are gradually added at this temperature while stirring. The reaction temperature is increased to + 10 ° C. with the gradual addition of 500 ml of water. The reaction mixture is filtered through kieselguhr and washed several times with ether. The ether phases are separated off and, after washing with hydrochloric acid (3 × 100 ml), saturated sodium chloride solution (3 × 100 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z, E) -4 (E) -pentadien-l-ol is a yellow oil. The alcohol consists of the 2 (E) and 2 (Z) isomers in a ratio of 2: 1.

c) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3 ~ methyl-

2 (E), 4 (E) -pentadiene-l-al and 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z), 4 (E) -pentadien-l- al 306 g of manganese dioxide and 750 ml of methylene chloride are mixed under argon with 66 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z, E), 4 (E) -pentadiene-l- ol in 500 ml of methylene chloride. The reaction mixture is stirred at 23 ° C. for 4 days under argon, then filtered through diatomaceous earth and washed with 2 l of methylene chloride. The 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (Z), 4 (E) -pentadien-l-al remaining after evaporation of the solvent] under reduced pressure is first of all by adsorption 800 g

Silica gel and then purified by preparative high pressure chromatography. After recrystallization from ether / petroleum ether, the aldehyde melts at 82-85 ° C. By further elution of the adsorption column, 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (E), 4 Isolate (E) -pentadiene-l-al. After recrystallization from ether / petroleum ether, this aldehyde melts at 61-63 ° C.

Example 3

A. 9- (4-methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (Z), 8 (E) -nonatetraenoic acid- methyl ester

1.152 g of sodium hydride (50% oil dispersion) is washed twice with 50 ml of pentane and then mixed with 25 ml of 1,2-dimethoxyethane (distilled over lithium aluminum hydride). 5.328 g of methyl 4- (dimethoxyphosphinyl) -3-methyl-crotonic acid in 25 ml of 1,2-dimethoxyethane are added dropwise to the mixture in 20 minutes under argon. The reaction mixture is stirred under argon at 23 ° C. for a further two hours and then dropwise with 6.288 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3-methyl-2 (Z) within 35 minutes. , 4 (E) -pentadien-l-al in 55 ml of 1,2-dimethoxyethane. The dark brown colored syrup is stirred under argon at 23 ° C. for 2.5 hours, then cooled, poured into 500 ml of ice water and neutralized with in hydrochloric acid (pH 5-6). After adding 200 ml of methylene chloride, the mixture is stirred for 5 minutes. The aqueous phase is separated off and extracted again with methylene chloride (3 × 200 ml). The combined methylene extracts are washed with water (3 x 100 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 9- (4-methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (Z), 8 (E) -nonatetraen Acid methyl ester is purified by adsorption on 300 g of silica gel [eluent: ether / petroleum ether (boiling range: 30-60 ° C.) (1: 9)]. After fractional crystallization from methylene chloride / petroleum ether (1: 4) or from acetone, the ester melts at 119-121.5 ° C.

B. 9- (4-methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl-2 (Z), 4 (E), 6 (Z), 8 (E) -nonatetraenoic acid- methyl ester The mother liquor from Example 3 is evaporated to dryness. The remaining oily 9- (4-methoxy-2,3,6-tri-methylphenyl) -6-fluoro ~ 3,7-dimethyl-2 (Z), 4 (E), 6 (Z), 8 (E ) -Nonatetraenic acid methyl ester melts after recrystallization from ether / petroleum ether (1: 1) at 134-139.5 ° C.

Example 4

9- (4-Methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid methyl ester 5 32 g of methyl 4- (dimethoxyphosphinyl) -3-methyl-crotonic acid are dissolved in 25 ml of dry 1,2-dimethoxyethane. The solution is added dropwise to a suspension of 1.152 g of sodium hydride (50% oil dispersion) in 25 ml of 1,2-dimethoxyethane. The reaction mixture obtained is stirred under argon at 25 ° C. for 1.5 hours, then in 6.288 g of 5- (4-methoxy-2,3,6-trimethyl) -2-fluoro-3-methyl-2 (E) , 4 (E) -pentadien-1-al added dropwise in 50 ml of 1,2-dimethoxyethane. The mixture is then stirred at 25 ° C. for 17 hours, then heated under argon under reflux conditions for a further hour, then cooled and introduced into 500 ml of water. The solution obtained is acidified by adding In aqueous hydrochloric acid (pH 3-4) and then extracted with methylene chloride (3 × 250 ml). The combined methyl chloride extracts are washed with water (3 x 100 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 9- (4-methoxy-2,3,6-trimethylphenyl) -6-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (E), 8 (E) -

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8th

Methyl nonatetraenate is purified by adsorption in 200 g of silica gel [eluent: ether / petroleum ether]. After recrystallization from methylene chloride / petroleum ether (1: 4) twice, the ester melts at 133-141 ° C. A sample of the ester intended for analysis melts at 139-143 ° C. after further recrystallization.

The 5- (4-methoxy-2,3,6-trimethyIphenyl) -2-fluoro-3-methyl-2 (Z), 4 (E) -pentadien-l-al used as the starting compound in Example 3 and that in Example 4 5- (4-methoxy-2,3,6-trimethyl-phenyl) -2-fluoro-3-methyl-2 (E), 4 (E) -pentadien-l-al used as the starting compound can e.g. B. can be produced as follows:

a) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -2 (Z, E) -fluoro-3-methyl-

2,4 (E) -pentadienoic acid ethyl ester

14.4 g of sodium hydride (50% oil dispersion) in 250 ml of 1,2-dimethoxyethane (distilled over lithium aluminum hydride) are added dropwise under argon in an ice bath within 30 minutes with stirring with 72.7 g of (diethoxyphos-phinyl) -fluoroacetic acid methyl ester in 80 ml 1,2-dimethoxyethane added. The mixture is stirred for a further two hours under argon at 23.0 ° C. The brown-colored mixture is added dropwise with 65.4 g of 4- (4-methoxy-2,3,6-trimethyl-phenyl) within 40 minutes after adding a further 70 ml of 1,2-dimethoxyethane with vigorous stirring at 23 ° C. 3-buten-2-one in 200 ml of 1,2-dimethoxyethane. A brown-colored syrupy precipitate separates out under an exothermic reaction. The mixture is first stirred for a further hour at 23 ° C. and then for 4 hours at 52-55 ° C., then cooled and 11 ice water added. The solution is adjusted to pH 4-5 by adding 1N hydrochloric acid and extracted with methylene chloride (3 × 250 ml). The combined methylene chloride extracts are washed with water (3 x 200 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 5- (4-methoxy-2,3,6-trimethyl-phenyl) -2 (Z, E) -fluoro-3-methyl-2,4 (E) -pentadienoic acid ethyl ester is by adsorption on 800 g of silica gel [Eluent: ether / petroleum ether (5:95)] purified. The ester is a yellow oil and consists of the two Z and two E isomers in a ratio of 3: 2.

b) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -2 (Z, E) -fluoro-3-methyl

2,4 (E) -pentadiene-l-ol

57.5 g of ethyl 5- (4-methoxy-2,3,6-trimethylphenyl) -2 (Z, E) -fluoro-3-methyl-2,4 (E) -pentadienate are dissolved in 1.201 absolute ether. The solution is cooled to −70 ° C. with stirring and under argon in an acetone / ice bath and an approx. 1.5 molar solution of isobutylaluminum hydride in hexane is added dropwise within 30 minutes. The temperature should not exceed -65 to -70 ° C. The course of the reaction is monitored by thin layer chromatography, which still indicates the presence of the starting substance. It will therefore be repeated

125 ml of diisobutylaluminum hydride are added and the mixture is stirred for a further 2 hours. After that, no starting material can be recognized in the thin-layer chromatogram. The mixture is then mixed with 500 ml of water / methanol (1: 1), stirred for a few minutes at 5-10 ° C., during which a precipitate separates out under an exothermic reaction. This is filtered off over kieselguhr and washed 4 times with 800 ml ether. The aqueous phase which separates from the combined filtrates (about 4.5 l) is extracted with 500 ml of ether. The ether extracts are washed with water (3 x 800 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 5- (4-methoxy-2,3,6-trimethylphenyl) -2 (Z, E) -fluoro-3-methyl-2,4 (E) -pentadien-l-ol melts after recrystallization from ether / Petroleum ether (1:30) at

49 ° C.

c) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3-methyl-

2 (Z), 4 (E) -pentadien-l-al and 5- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3-methyl-

2 (E), 4 (E) -pentadiene-l-aI 53.5 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -2- (Z, E) -fluoro-3-methyl-2 , 4 (E) -pentadien-l-ol are dissolved in 300 ml of methylene chloride. 200 g of manganese dioxide in 800 ml of methylene chloride are added to the solution in portions under argon. The reaction mixture is stirred in the dark for 3 days, after adding 100 g of manganese dioxide for a further 4 days under argon, then filtered through diatomaceous earth and washed with about 1.51 methylene chloride. The slightly brown colored 5- (4-methoxy-2,3,6-tri-methylphenyl) -2-fluoro-3-methyl-2 (E), 4 (E) -pentadiene remaining after evaporation of the solution under reduced pressure -l-al is purified by adsorption on 1.4 kg of silica gel [eluent: diethyl ether / hexane (1: 9)]. The aldehyde melts after recrystallization from ether / petroleum ether (1: 1) at 79-84 ° C.

Further elution of the adsorption column with diethyl ether / hexane (1: 4) gives 5- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3-methyl-2 (Z), 4 (E) - pentadien-l-al. The aldehyde obtained melts at 87-91 ° C and after recrystallization from ether twice at 89-93 ° C.

Example 5

A. 9- (4-methoxy-2,3,6-trimethylphenyl) -4-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid-

ethyl ester and

B. 9- (4-Methoxy-2,3,6-trimethylphenyl) -4-fluoro-3,7-dimethyl-2 (E), 4 (Z), 6 (E), 8 (E) -nonatetraenoic acid

ethyl ester

4.88 g of ethyl 4- (diethoxyphosphinyl) -4-fluoro-3-methyl-crotonate are dissolved in 20 ml of 1,2-dimethoxyethane. The solution is added dropwise under argon at 23 ° C. to a suspension of 1.25 g of sodium hydride (50% oil dispersion) in 60 ml of dry 1,2-dimethoxyethane (distilled over lithium aluminum hydride). The reaction mixture is first stirred at 23 ° C. for 10 minutes and then under argon for 14 hours under reflux conditions. The mixture is then cooled to 35-40 ° C. over the course of 1 hour and added dropwise with 4.23 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (E) over the course of 30 minutes. , 4 (E) -pentadien-l-al in 20 ml of 1,2-dimethoxyethane. The slightly brown-colored reaction mixture is then heated under argon, first for 1.5 hours at 23 ° C., then for 45 minutes under reflux conditions, then cooled and introduced into about 400 ml of ice water. The resulting solution is adjusted to a pH of about 2 by adding in aqueous hydrochloric acid and, after adding 250 ml of methylene chloride, stirred for about 10 minutes. The aqueous phase is separated off and extracted again with methylene chloride (3 × 150 ml). The combined methylene chloride extracts are washed with water (2 x 100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The remaining oily, brown 9- (4-methoxy-2,3,6-trimethylphenyl) -4-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (E), 8 (E) -Nonatetraenoic acid ethyl ester is purified by adsorption in 700 g silica gel [eluent: ether / petroleum ether (5:95)]. The ester obtained melts at 76-83 ° C and after recrystallization from petroleum ether at 78-84 ° C.

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Further elution of the adsorption column with 5-10 tiger ether in petroleum ether gives 9- (4-methoxy-2,3,6-trimethylphenyl) -4-fluoro-3,7-dimethyl-2 (E), 4 (Z) , 6 (E), 8 (E) -nonatetraenoic acid ethyl ester which melts at 84-93 ° C and after recrystallization from ether at 92.5-96.5 ° C.

Example 6

9- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-7-

trifluoromethyl-2 (E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid methyl ester

750 mg of methyl 4- (dimethoxyphosphinyl) -3-methyl-crotonic acid are dissolved in 5 ml of 1,2-dimethoxyethane. The solution is introduced at 0 ° C. into a suspension of 116 mg sodium hydride (50% oil dispersion) in 5 ml dry 1,2-dimethoxyethane. The reaction mixture is first stirred under argon for 10 minutes at 0 ° C., then for 1 hour at 300 ° C., then in 15 g in 1.0 g of 5- (4-methoxy ~ 2,3,6-trimethylphenyl) -3-trifluoromethyl -2 (E), 4 (E) -pentadien-l-al in 5 ml of 1,2-dimethoxyethane,

Stirred at 23 ° C for 3 hours and heated under reflux conditions for a further 30 minutes. The mixture is then cooled and poured into 250 ml of ice water. The solution is brought to a pH of by adding aqueous in hydrochloric acid

4 adjusted and extracted with methylene chloride (4 x 50 ml). The combined methylene chloride extracts are washed with water and with a saline solution, then dried over magnesium sulfate and evaporated under reduced pressure. The remaining 5- (4-methoxy-2,3,6-trimethyl-phenyl) -3-trifluoromethyl-2 (E), 4 (E) -pentadien-l-al is by adsorption in 25 g of silica gel [eluent: ether / • Petroleum ether (5:95)] cleaned. Further elution of the adsorption column with 5% ether in petroleum ether gives 9- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-7-trifluoromethyl-2 (E), 4 (E), 6 (E) -Nonatetraenoic acid methyl ester. After recrystallization from petroleum ether, the ester melts at 112-113.5 ° C.

The 5- (4-methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-2 (E), 4 (E) -pentadien-l-al used as starting material in Example 6 can e.g. can be produced as follows:

a) Preparation of 4- (4-methoxy-2,3,6-trimethylphenyl) -1,1,1-trifluoro-2-butyn-4-ol

10.6 g of magnesium metal in 1.01 dry ether are added dropwise with 43.4 g of methyl bromide under argon over the course of an hour. The reaction mixture is heated under reflux conditions for 1.5 hours and then cooled to 23 ° C. The formed ethyl magnesium bromide is mixed with 41.0 g of trifluoropropyne. The reaction mixture is stirred at 23 ° C. under argon, the trifluoropropyne being recycled three times. The resulting brown, oily trifluoropropylmagnesium bromide is mixed with 50 g of 2,3,6-trimethyl-4-methoxy-benzaldehyde under argon over 30 minutes at 23 ° C. with vigorous stirring. The mixture is stirred at 23-30 ° C for 2 hours. After adding a further 10 g of 2,3,6-trimethyl-4-methoxy-benzaldehyde in 100 ml of ether, the mixture is stirred for a further hour, then cooled and carefully added to a saturated aqueous ammonium chloride solution while stirring. The phases that form are separated. The aqueous phase is extracted three times with ether. The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 4- (4-methoxy-2,3,6-trimethyl-phenyl) -l, l, l-trifluoro-2-butyn-4-ol melts after recrystallization twice from chloroform / hexane at 126-130 ° C. The analytically pure substance melts at 127-129.5 ° C.

b) Preparation of 4- (4-methoxy-2,3,6-trimethylphenyl) -l, l, l-trifluoro-

3 (E) -buten-2-one 92 mg mercury sulfate and 0.05 ml concentrated sulfuric acid in 5 ml glacial acetic acid are dissolved in a solution of 277 mg 4- (4-methoxy-2,3,6-trimethyIphenyI) -l, l , l-trifluoro-2-butyn-4-ol in 10 ml of glacial acetic acid. The mixture is heated under reflux conditions for 2 hours, then poured into 150 ml of ice water and extracted with ether (3 x 40 ml). The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 4- (4-methoxy-2,3,6-trimethylphenyl) -l, l, l-trifluoro-3 (E) -buten-2-one melts after recrystallization twice from petroleum ether at 79-82 ° C.

c) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-

Methyl 2 (E), 4 (E) -pentadienate 20.08 g of methyl (dimethoxyphosphinyl) acetic acid in 50 ml of 1,2-dimethoxyethane are added dropwise at 0 ° C. to a suspension of 4.92 g of sodium hydride (50% Oil dispersion) entered in 200 ml of 1,2-dimethoxyethane. The reaction mixture is stirred under argon at 23 ° C for 2 hours, then dropwise with a solution of 25 g (4- (4-meth-oxy-2,3,6-trimethylphenyl) -l, l, l-trifluoro-3 ( E) ~ buten-2-one in 200 ml of 1,2-dimethoxyethane, the mixture is stirred for half an hour at 23 ° C., then heated under reflux conditions for 2 hours, then cooled in an ice bath and added to 1.01 ice water. The solution obtained is adjusted to pH 7 by adding 2N aqueous hydrochloric acid and then extracted with methylene chloride (3 × 200 ml), the combined methylene chloride extracts are washed with water and with a saline solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure 5- (4-Methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-2 (E), 4 (E) -pentadienoic acid methyl ester is obtained by adsorption on 700 g silica gel [eluent: 3% ether in petroleum ether The ester melts after recrystallization at -72 ° C s Pentane at 42-48 ° C.

d) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-

2 (E), 4 (E) -pentadien-1-ol 69.5 ml of a 1.53 molar solution of dimethylisobutyl aluminum hydride in hexane are a solution of 17.44 g of 5- (4th -Methoxy-2,3,6-tri-methylphenyl) -3-trifluoromethyl-2 (E), 4 (E) -pentadienoic acid methyl ester added dropwise in 500 ml of dry ether. The resulting solution is stirred under argon at -72 ° C for 20 minutes, then another 25 ml of diisobutyl aluminum hydride is added and the mixture is stirred at -72 ° C for a further 30 minutes. The resulting yellow solution is mixed with 100 ml of methanol / water 1: 1 at -72 ° C and gradually warmed to 23 ° C with stirring. The precipitate is separated off and washed well with ether. The ether phase is separated off and washed with water and a saline solution, dried over magnesium sulfate and evaporated under reduced pressure. The remaining 5- (4-methoxy-2,3,6-trimethyl-phenyl) -3-trifluoromethyl-2 (E), 4 (E) -pentadien-l-ol melts after recrystallization from petroleum ether at 69-71 ° C.

e) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl

2 (E), 4 (E) -pentadien-l-al A mixture of 78 g manganese dioxide and 13 g 5- (4-meth-oxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-2 (E) , 4 (E) -

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Pentadien-l-ol in 750 ml dry methylene chloride is stirred under argon at 23 ° C for 15 hours. The mixture is then filtered through diatomaceous earth and washed with a total of 1.01 methylene chloride. The methylene chloride is evaporated under reduced pressure. The remaining oily 5- (4-methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-2 (E), 4 (E) -pentadien-l-al is by adsorption on 600 g of silica gel [eluent: 5 % Ether in petroleum ether]. The aldehyde melts after recrystallization from pentane at 55-58 ° C.

Example 7

9- (4-Methoxy-2,3,6-trimethylphenyl) -4-fluoro-3,7-dimethyl-2 (E), 4 (Z), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester 2 , 37 g of sodium hydride (50% oil dispersion) are added dropwise at 23 ° C with 11.08 g of (diethoxyphosphinyl) acetic acid ethyl ester after adding 10 ml of dry dimethoxyethane [distilled over bis- (2-methoxyethoxy) sodium aluminum hydride] 30 ml of dry dimethoxyethane are added. The mixture is stirred at 23 ° C. until no more hydrogen escapes, which is the case after about 1 hour, then dropwise at 23 ° C. with 10 g of 8- (4-methoxy-2,3,6-trimethylphenyl) -3-fluoro-6-methyl-3 (Z), 5 (E), 7 (E) -octatrien-2-one in 75 ml of dimethoxyethane. After the entry has ended, the reaction mixture is stirred for a further 0.5 hours at 23 ° C. and under argon for a further 2 hours at 50 ° C. Thin layer chromatography shows that no starting material is present. The reaction mixture is then cooled to about 20 ° C. and first introduced into 200 ml of cold water and then into ice. The mixture is adjusted to pH 4 by dropwise addition of concentrated hydrochloric acid, then extracted three times with 200 ml ether. The combined ether extracts are washed three times with 200 ml of water each time, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product is purified by adsorption in 200 g of silica gel [eluent: 10% ether / petroleum ether]. The eluates are evaporated under reduced pressure at approx. 40 ° C. The residue is taken up in 300 ml of methylene chloride and, after addition of 10 g of norit, heated for 2 minutes on a steam bath, then filtered and washed with 400 ml of methylene chloride. The yellow crystals remaining after evaporation of the methylene chloride at 35-40 ° C / 20-30 torr is dissolved in 25 ml of ether with the addition of 1 ml of methylene chloride. The solution is diluted with 50 ml of petroleum ether (boiling range: 30-60 ° C) and remains at 23 ° C for a few hours, then at 0-4 ° C for 18 hours. The crystallizing 9- (4-methoxy-2,3,6-trimethyl-phenyl) -4-fluoro-3,7-dimethyl-2 (E), 4 (Z), 6 (E), 8 (E) - ethyl nonate-traenate is washed with 50 ml of petroleum ether and dried.

The 8- (4-methoxy-2,3,6-trimethylphenyl) -3-fluoro-6-methyl-3 (Z), 5 (E), 7 (E) -octatrien-2- one can e.g. B. can be produced as follows:

a) Preparation of 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-5-methyl-

2 (Z, E), 4 (E), 6 (E) ~ heptatrienoic acid ethyl ester 20.16 g sodium hydride (50% oil dispersion) in 250 ml dry dimethoxyethane are added dropwise with 79.92 g ( Diethoxyphosphinyl) -fluoro-acetic acid ethyl ester added. The reaction mixture is stirred under argon at 40 ° C for 1 hour, then cooled to room temperature. The resulting yellow-orange mixture is added dropwise with 75 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 (E), 4 (E) -pentadiene-1 with stirring and gassing with argon -al added in 500 ml of dry dimethoxyethane. The mixture is stirred at 23 ° C for 2 hours, then heated to 40 ° C for 2 hours, then to about 20 ° C

cooled, added to 500 ml of ice water and adjusted to pH 4 with stirring by adding in hydrochloric acid. The solution is extracted four times with 500 ml ether each time. The combined ether extracts are washed four times with 500 ml of water, then with 500 ml of saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining dark orange colored oil is purified by adsorption on 2.2 kg of silica gel [eluent: ether / petroleum ether (10:20)]. The oily ester obtained consists of the E and Z isomers in a ratio of 3: 2. By further elution of the adsorption column with 40% ether, unreacted starting material is obtained. The resulting mixture of isomers of the esters is used without further purification for the preparation of 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-5-methyl-2- (Z), 4 (E), 6 ( E) -heptadienoic acid ethyl ester used.

b) Preparation of 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-5-methyl-

2 (Z), 4 (E), 6 (E) -heptatrienoic acid ethyl ester 66.1 g 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-5-methyl-2 (Z, E), 4 (E), 6 (E) -heptatrienic acid ethyl ester (E: Z ~ 3: 2) are dissolved in 600 ml of dry ether. The solution is mixed in portions with 1.4 g of crystalline iodine, stirred for 48 hours under argon at 23 ° C., then washed three times with 200 ml of a 5% sodium thiosulfate solution, then twice with 200 ml of water and then dried over anhydrous magnesium sulfate. The ether solution is evaporated under reduced pressure. The remaining concentrate is purified by adsorption on 100 g of silica gel [eluent: 1.5 1 ether]. The ether solution is evaporated, the residue is redissolved in 100 ml ether. The solution is diluted with 600 ml of petroleum ether (boiling range: 30-60 ° C) and remains after 1 hour at 23 ° C, 3 hours at 0 ° C. The 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-5-methyl-2 (Z), 4 (E), 6 (E) -heptatrienoic acid ethyl ester deposited in yellow crystals melts after washing with cold petroleum ether at 106-110 ° C.

The oil remaining after evaporation of the mother liquor is taken up in 750 ml of ether, after adding 0.83 g of iodine crystals under argon, stirred for 70 hours at 23 ° C. and then worked up as described above. The yellow crystalline 7- (4-methoxy-2,3,6-trimethylphenyl) 2-fluoro-5-methyl-2 (Z), 4 (E), 6 (E) -heptatrienoic acid ethyl ester melts at 109-111 ° C.

c) Preparation of 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-5-methyl-

2 (Z), 4 (E), 6 (E) -pentatrienoic acid 41.5 g 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluorine-5-methyl-2 (Z), 4 (E), 6 (E) -heptatrienic acid ethyl ester are dissolved in 450 ml of tetrahydrofuran. The solution is mixed with 150 ml of methanol and 40 ml of a 6N sodium hydroxide solution and stirred for 15 minutes at 23 ° C., the white precipitate which precipitates is brought into solution by adding 500 ml of water. The solution is stirred at 23 ° C for 1 hour. The largest amount of tetrahydrofuran and methanol is then evaporated at 50 ° C under reduced pressure. The concentrate is diluted with 150 ml of water and extracted twice with 200 ml of ether each time. The alkaline aqueous phase is cooled to 0-4 ° C., adjusted to a pH of 3-4 by adding concentrated hydrochloric acid and extracted three times with 300 ml of ether each time. The combined ether extracts are washed twice with 200 ml of water and once with 200 ml of brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining yellow crystalline 7- (4-methoxy-2,3,6-

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trimethylphenyl) -2-fluoro-5-methyl-2 (Z), 4 (E), 6 (E) -heptatrienic acid melts at 203-210 ° C.

d) Preparation of 8 - (4-methoxy-2,3,6-trimethylpheny 1) -3-fluoro-6-methyl-

3 (Z), 5 (E), 7 (E) -octatrien-2-one 37.82 g 7- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-5-methyl-2 ( Z), 4 (E), 6 (E) -heptatrienoic acid is dried in a desiccator over phosphorus pentoxide for 24 hours at about 0.5 torr, then dissolved in 400 ml of dry tetrahydrofuran and added dropwise in an acetone / ice bath under argon and vigorous stirring -72 ° C with 154 ml of a 1.61 molar solution of methyl lithium in ether. The reaction mixture is stirred at -75 ° C under argon for 15 minutes. The course of the reaction is monitored using thin-layer chromatography. After adding another 15.4 ml of methyl lithium, the reaction mixture is stirred at -75 ° C for 1 hour. After that, no free acid is present. After removing the cooling bath, the reaction mixture is carefully mixed with 150 ml of water. Most of the tetrahydrofuran is evaporated at 50 ° C, 30-50 Torr. The aqueous solution is extracted three times with 300 ml ether. The combined ether extracts are washed three times with 300 ml of water each time, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is taken up in 50 ml of methylene chloride and diluted with 300 ml of hexane. The 8- (4-methoxy-2,3,6-trimethylphenyl) -3-fluoro-6-methyl-3 (Z), 5 (E), 7 (E) -octatrien- 2-one melts after washing with cold hexane at 108-110 ° C. Another amount of the orange colored crystalline ketone melting at 107-110 ° C can be obtained from mother liquors.

Example 8

9- (4-Methoxy-2,3,6-trimethylphenyl) -8-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (E), 8 (Z) -nonatetraenoic acid methyl ester 1 , 41 g of sodium hydride (50% oil dispersion) in 60 ml of dry dimethoxyethane is added dropwise with stirring with 6.06 g of methyl 4- (dimethoxyphosphinyl) -3-methyl-crotonic acid in 30 ml of dimethoxyethane. The mixture is stirred at 23 ° C. until the evolution of hydrogen has subsided, after the addition of 6.0 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-4-fluoro-2 (E), 4 (Z) -pentadien-l-al in 30 ml of dimethoxyethane was stirred for 1.6 hours at 23 ° C. under argon and then carefully introduced into about 500 ml of ice water. The solution is adjusted to pH 1 by adding 6N hydrochloric acid and immediately extracted with ether. The 9- (4-methoxy-2,3,6-trimethylphenyl) -8-fluoro-3,7-dimethyl-2 (E), 4 (E), 6 (E), 8 ( Z) -Nonatetraenic acid methyl ester is purified by adsorption on 500 g of silica gel [eluent: ether / petroleum ether (1: 9)]. The yellow crystalline ester consisting of a mixture of the two isomers melts at 121.5 ° C.

The 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-4-fluoro-2 (E), 4 (Z) -pentadien-l-al used as starting material in Example 8 can e.g. can be produced as follows:

a) Preparation of 3- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-2 (Z, E) -

Ethyl propenate A solution of 60 g (diethoxyphosphinyl) -fluoro-acetic acid ethyl ester in 50 ml dimethoxyethane is at 23 ° C in the course of 2 hours in a suspension of 17.8 g sodium hydride (50% oil dispersion) in 150 ml dropped in dry dimethoxyethane. The reaction mixture is stirred at 23 ° C. for 3 hours. As soon as the evolution of hydrogen has subsided, 44 g of 2,3,6-trimethylanisaldehyde in 50 ml of dry dimethoxyethane are added over the course of 15 minutes. The mixture is stirred at 23 ° C for 20 hours. A further 20 g (ethyl ethoxyphosphinyl) -fluoroacetic acid in 20 ml of dimethoxyethane are then added in portions over the course of 1.5 hours with stirring and with argon gassing. After the mixture has cooled to about 30 ° C., 1.92 g of sodium hydride (50% oil suspension) and 5.0 g (diethoxyphosphinyl) -fluoroacetic acid ethyl ester in 10 ml of dimethoxyethane are added. The mixture is stirred for a further 30 minutes. Thin layer chromatography indicates the end of the reaction. The mixture is then cooled to about 4 ° C and added to 11 ice water. The resulting solution is adjusted to pH 2 by adding 150 ml of hydrochloric acid, then extracted three times with 400 ml of methylene chloride. The combined methylene chloride extracts are washed five times with 500 ml of water and once with 250 ml of brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining brown oily 3- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-2 (Z, E) propenoic acid ethyl ester is adsorbed on 1.5 kg silica gel [eluent: ether / Petroleum ether (1: 19-1: 9)] cleaned.

b) production of

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

2 (Z, E) propenoic acid

A solution of 78.1 g of 3- (4-methoxy-2,3,6-trimethyl-phenyl) -2-fluoro-2- (Z, E) propenoic acid ethyl ester in 150 ml of ethanol is added dropwise with 97.7 ml of aqueous 6N sodium hydroxide solution are added. A thick white precipitate separates out. The mixture is stirred intensively at 23 ° C. for 30 minutes, then diluted with 11 ice water and adjusted to a pH of 1 by adding about 50 ml of concentrated hydrochloric acid. The white precipitate is extracted three times with 400 ml ether. The combined ether extracts are washed once with 500 ml of saline, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining white 3- (4-methoxy-2,3,6-trimethyl) -2-fluoro-2 (Z, E) propenoic acid melts after drying for several days at 23 ° C over phosphorus pentoxide at 163-181 ° C.

c) Manufacture of

4- (4-methoxy-2,3,6-trimethylphenyl) -3-fluoro-3 (Z) -buten-2-one

25 g of 3- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-2 (Z, E) propenoic acid are dissolved in 35 ml of dry tetrahydrofuran and 250 ml of anhydrous ether, to -70 ° C in one Cooled ice / acetone bath and carefully added 47.5 g of a 2.23 molar solution of methyl lithium in ether under argon and vigorous stirring. The internal temperature should be between -60 ° C and -70 ° C. The mixture is stirred under argon at -70 ° C for 10 minutes, then another 47.5 ml of methyl lithium are added, the mixture is stirred again at -70 ° C for 1 hour, another 5 ml of methyl lithium is added and the mixture is stirred for a further 10 minutes. The mixture is then carefully introduced into 500 ml of ice water, adjusted to a pH of 1 by adding concentrated hydrochloric acid and extracted with ether. The oily 4- (4-methoxy-2,3,6-trimethylphenyl) -3-fluoro-3 (Z) -butene-2-one remaining after evaporation of the ether and the white starting material which precipitates out is adsorbed on 1, 6 kg silica gel [eluent: ether / petroleum ether (1: 9)] cleaned. The initially isolated isomeric ketone melts at 56-59 ° C.

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624 373

After further elution, the Z isomer 4- (4-meth-oxy-2,3,6-trimethylphenyl) -3-fluoro-3 (Z) -buten-2-one is obtained.

d) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-4-fluoro-

2 (E), 4 (Z) -pentadienic acid ethyl ester • 26.84 g (diethoxyphosphinyl) acetic acid ethyl ester are in the course of 25 minutes in a suspension of 5.75 g sodium hydride (50% oil dispersion) in 200 ml dry dimethoxyethane dropped in. The mixture is stirred for 1 hour at 23 ° C., after dropwise addition of 23.53 g of 4- (4-methoxy-2,3,6-trimethylphenyl) -3-fluoro-3 (Z) -buten-2-one in 100 ml of dimethoxyethane were stirred under argon at 23 ° C. for 1.25 hours, then carefully introduced into about 11 ice water and adjusted to pH 2 by adding 6N hydrochloric acid. The reaction mixture is then extracted with ether and worked up in a conventional manner. The ethyl 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-4-fluoro-2 (E), 4 (Z) -pentadienoate is obtained by adsorption on 600 g of silica gel [eluent : Ether / petroleum ether (1: 19-1: 9)] cleaned. The white crystalline ester melts at 50-51 ° C.

e) Preparation of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-4-fluorine

2 (E), 4 (Z) -pentadien-1-ol 86.5 ml of a 1.5 molar solution of diisobutylaluminum hydride in hexane are added dropwise at −65 ° C. under argon to a solution of 14.48 g of 5- ( 4-Methoxy-2,3,6-tri-methylphenyI) -3-methyl-4-fluoro-2 (E), 4 (Z) -pentadienoic acid ethyl ester in 400 ml of anhydrous ether. The mixture is stirred under argon at 65 ° C for 5 minutes, after adding a further 17 ml of diisobutylaluminum hydride in two portions at 20 ° C for another 20 minutes. The excess diisobutyl aluminum hydride is destroyed by dropwise addition of 85 ml of methanol / water 1: 1 at about -30 ° C. The mixture is diluted with 100 ml of water and stirred at 10 ° C. for 40 minutes. The precipitate that forms is filtered off and washed with ether. The water phase is separated off and extracted with ether. The combined ether extracts are washed successively with water and with a saline solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is taken up in 215 ml of ether and diluted with 50 ml of petroleum ether (boiling range: 30-60 ° C). The 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-4-fluoro-2 (E), 4 (Z) -pentadiene-l- which crystallizes after 20 hours at -10 ° C. oil melts at 71-73 ° C.

f) Preparation of 5- (4-methoxy ~ 2,3,6-trimethylphenyI) -3-methyl-4-fIuor-

2 (E), 4 (Z) -pentadiene-l-al 13.84 g 5- (4-methoxy-2,3,6-trimethylphenyl-3-methyl-4-fluoro-2 (E), 4 (Z ) -pentadien-l-ol are dissolved in 55 ml of methylene chloride. The solution is introduced with stirring into a mixture of 57.66 g of manganese dioxide in 60 ml of methylene chloride. The mixture is stirred under exclusion of light, under argon for 65 hours and worked up in a conventional manner The 5- (4-methoxy-2,3,6-trimethylphenyl) - obtained

3-methyl-4-fluoro-2 (E), 4 (Z) -pentadien-l-al melts after recrystallization from methylene chloride / petroleum ether 1: 4 at 85-88.5 ° C. The analytically pure aldehyde melts at 86. 5-88.5 ° C.

Example 9

9- (4-Methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl 7-methyl-2 (E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid ethyl ester 9.44 g Ethyl 4- (diethoxyphosphinyl) -2 (Z, E) -3- (trifluoromethyl) -crotonic acid in 50 ml of dimethoxyethane is added dropwise to a suspension of 1.42 g of sodium hydride (50% oil dispersion) in 25 ml of dimethoxyethane at 0 ° C entered. The mixture is stirred at 23 ° C. for about 1 hour until the evolution of hydrogen stops, then dropwise under argon with 6.59 g of 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2 ( E), 4 (E) -pentadien-l-al in 50 ml of dimethoxyethane. The reaction mixture is stirred for 5 hours under argon at 23 ° C., then introduced into ice water, adjusted to pH 3 by adding 2N hydrochloric acid and extracted three times with 250 ml ether. The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The remaining 9- (4-meth-oxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-7-methyl-2 (E), 4 (E), 6 (E), 8 (E) -nonatetraenoic acid- ethyl ester is purified by adsorption on 300 g of silica gel [eluent: ether / petroleum ether (1:19)]. The compound melts after recrystallization from ether at 72-75 ° C.

The one used as the starting compound in Example 9

4- (Diethoxyphosphinyl) -2 (Z, E) -3- (trifluoromethyl) -crotonic acid ethyl ester can e.g. B. can be produced as follows:

18.48 g of ethyl 3-trifluoromethyl-4-bromo-2 (Z, E) -butenate and 12.95 g of triethyl phosphite are heated at 140 ° C. for 3 hours. The ethyl bromide which forms is continuously distilled off during the reaction. The 4- (di-ethoxyphosphinyl) -2 (Z, E) -3- (trifluoromethyl) -crotonic acid ethyl ester obtained, a mixture of the two isomers, boils at 110-113 ° C. after rectification.

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Claims (11)

624 373 2. The method according to claim 1, characterized in that an esterified compound of the formula I in which R9 is carboxy is esterified. 2nd PATENT CLAIMS 1. Process for the preparation of new polyene compounds of the general formula R in the R 1, R 2 and R 3 lower alkyl, R4 lower alkoxy, R6 and R8 methyl or trifluoromethyl, R9 formyl, hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxycarbonyl, lower alkenoxycarbonyl, lower alkynoxycarbonyl, carbamoyl, mono ( lower alkyl) carbamoyl, diveder alkylcarbamoyl or Represent N-heterocyclylcarbonyl and Rs, R7, R10, Ru, R12 and R13 denote hydrogen or fluorine; with the restriction that at least one of the radicals R5, R7, R10, Ria, R12 and R13 is fluorine or at least one of the radicals R6 or R8 is trifluoromethyl, and of pharmaceutically acceptable salts of these compounds, characterized in that a compound of the general formula IIa with a compound of the general formula 14 III; implements, or that a compound of the general formula _ "_. Rn Rr R- A IIb with a compound of the general formula L8 implemented, or that a connection of the general For-15 mei HC Illb 25 with a compound of the general formula 35 40 50 60 R 14 30th * R IIIc 3. The method according to claim 1, characterized in that one obtains a compound of formula I obtained, in which R9 is carboxy, amidated. 4. The method according to claim 1, characterized in that a compound of the formula I obtained, in which R9 is carboxy, is converted into a salt. 5. The method according to claim 1, characterized in that a compound of the formula I obtained, in which R9 is alkoxycarbonyl, lower alkenoxycarbonyl or lower alkynoxycarbonyl, is saponified to give the corresponding carboxylic acid. 6-methyl-3,5,7-octatrien-2-one with (diethoxyphosphinyl) acetic acid ethyl ester. 6. The method according to claim 1, characterized in that 5- (4 ~ methoxy-2,3,6-trimethylphenyl) -3-methyl-penta-2,4-dien-l-al with 4- (diethoxyphosphinyl) - 2-fluoro-3-methyl-crotonic acid ethyl ester or with 4- (diethoxyphos-phinyl) -2-fluoro-3-methyl-crotonic acid ethyl ester. 624 373 7. The method according to claim 1, characterized in that 5- (4-methoxy-2,3,6-trimethylphenyl) -2-fluoro-3-methyl-penta-2,4-diene-l-al with 4- (Dimethoxyphosphinyl) -3-methyl-crotonic acid methyl ester. 8. The method according to claim 1, characterized in that 5- (4-methoxy-2,3,6-trimethylphenyl) -3-trifluoromethyl-penta-2,4-diene-l-al with 4- (dimethoxyphosphinyl ) -3-methyl-crotonic acid methyl ester. 9. The method according to claim 1, characterized in that 8- (4-methoxy-2,3,6-trimethylphenyl) -3-fluorine 10. The method according to claim 1, characterized in that 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-4-fluoro-2,4-pentadiene-l-al with 4- (dimethoxyphosphinyl ) -3-methyl-crotonic acid methyl ester. 10th implements ® where in the formulas IIa, IIb, Ile and lilac, Illb, IIIc one of the radicals A and B is the oxo group, and the other radical is either a triaiylphosphonium group of the formula -P [Y] + 3Z ~, in the Y aryl and Z the anion is an inorganic or organic acid, or represents a dialkoxyphosphinyl group of formula -P [X] 2 in which X is alkoxy; Rt, R2, O R3, R4, Rs, R6, R7, R8, R10, Rh, R12 and R13 have the meaning given for the formula I, R14 denotes alkoxymethyl, dialkoxymethyl, alkanoyloxymethyl, alkoxycarbonyl, alkenoxycarbonyl or alkynoxycarbonyl when B represents the oxo group; and R14 means formyl, hydroxymethyl, alkoxymethyl, dialkoxymethyl, carboxyl, alkoxycarbonyl, alkenoxycarbonyl or alkynoxycarbonyl when B represents a triarylphosphonium or a dialkoxyphosphinyl group, and hydrolyzed an obtained acetal. 11. The method according to claim 1, characterized in that 5- (4-methoxy-2,3,6-trimethylphenyl) -3-methyl-2,4-pentadien-l-al with 4- (diethoxyphosphinyl) -3- (tri-fluoromethyl) -crotonic acid ethyl ester. mei