JPS6160062B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to polyene compounds, and more particularly to fluorinated aromatic polyene compounds, processes for their production, and pharmaceutical formulations containing them. The polyene compounds provided by the present invention have the formula [wherein R ₁ , R ₂ and R ₃ are lower alkyl, R ₄ is lower alkoxy, R ₆ and R ₈ are methyl or trifluoromethyl, R ₉ is lower alkoxycarbonyl, R ₅ , _R7 ,
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are hydrogen or fluorine, and at least one of R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is fluorine, or R ₆
and at least one of R ₈ is trifluoromethyl]. The compounds represented by the formula can occur as cis/trans mixtures, which can be separated into cis and trans compounds or isomerized entirely to trans compounds by conventional means, and then It is manufactured as follows. As used herein, the term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 2
-methyl-propyl, etc., and the term "lower alkoxy" refers to alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, isopropoxy, etc. All of the formulas presented include cis/trans and all-trans isomers with respect to the double bond on the polyene side chain. Examples of polyene compounds within the scope of this invention are as follows. 9-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-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-2
(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-2,3,6-trimethylphenyl)-3-methyl-7-trifluoro Methyl-2(E),4(E),6(E),8(E)-nonatetraenoic acid methyl ester, 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl -5-fluoro-
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 ethyl ester, 9-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-7-methyl-2,4,6,8- Nonatetraenoic acid ethyl ester, 9-(4-methoxy-2,3,6-trimethylphenyl)-8-fluoro-3,7-dimethyl-2
(E),4(E),6(E),8(Z)-nonatetraenoic acid methyl ester, 9-(4-methoxy-2,4,6-trimethylphenyl)-3-trifluoromethyl-7- Methyl-2(E),4(E),6(E),8(E)-nonatetraenoic acid ethyl ester. The compounds represented by the formula are of pharmacological value. They can be used for the local and systemic therapy of benign and malignant neoplasia and precancerous lesions, and for the systemic and local prevention of these conditions. The compounds of this invention are relatively non-toxic. The tumor suppressive effect of this compound is significant. In the papilloma test, tumors induced by dimethylbenzanthracene and croton oil regress. The following table shows the activity and toxicity of the compounds of the invention.

【table】

Table 1 The compounds of the formula can be used as medicaments in the form of pharmaceutical preparations containing them together with compatible carrier substances. Pharmaceutical formulations for systemic administration are prepared, for example, by incorporating a compound of the formula as the active ingredient into the pharmaceutically acceptable, non-toxic, solid or liquid and inert carriers customary in this type of formulation. can do. The pharmaceutical preparations can be used enterally, parenterally or topically. Preparations suitable for enteral administration are, for example, tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. Pharmaceutical formulations suitable for parenteral administration are infusion solutions. The appropriate amount at which a compound is administered can vary depending on the mode and route of administration and depending on the needs of the patient. For example, the compound can be administered in an amount of 25 mg to 100 mg per day, either in one dose or in divided doses. The pharmaceutical preparations can contain, in addition to the active compounds of the invention, pharmaceutically acceptable inert or pharmacologically active additives. The tablets or granules may contain, for example, a range of pharmaceutically acceptable binders, fillers, carrier substances or diluents. Liquid preparations can take the form of sterile, water-miscible solutions, for example. Capsules may contain pharmaceutically acceptable fillers or thickeners. Additionally, pharmaceutically acceptable aroma-improving additives, as well as pharmaceutically acceptable substances commonly used as preservatives, stabilizers, moisture retainers or emulsifiers, permeation pressure modifying salts, buffering agents, and the like; Other pharmaceutically acceptable additives may also be present in the pharmaceutical composition. The pharmaceutically acceptable carrier materials and diluents mentioned above are those well known in the pharmaceutical compounding art, such as organic or inorganic substances such as water, gelatin, lactose, magnesium stearate, talc, gum arabic, polyalkylene glycols, etc. It can be done. It is, of course, provided that all auxiliaries used in the production of pharmaceutical formulations are non-toxic and pharmaceutically acceptable. For topical administration, the compounds of the invention are conveniently formulated into ointments, tinctures, creams, solutions, lotions, sprays, suspensions, and the like. Ointments, creams and solutions are preferred. These pharmaceutical formulations for topical administration contain the compounds of the invention as active ingredients in pharmaceutically acceptable, non-toxic, inert, solid or liquid materials customarily used in formulations of this type and suitable for topical administration. It can be produced by mixing with a carrier. Common pharmaceutically acceptable antioxidants such as tocopherols, N-methyl-γ-tocophemilan, etc.
Butylated hydroxyanisole or butylated hydroxytoluene can also be incorporated into pharmaceutical formulations containing the compounds of the invention. According to the method provided by the present invention, the polyene compound of the above-mentioned formula is prepared by the general formula The compound with the general formula or the general formula The compound with the general formula or the general formula The compound with the general formula [However, in the above formulas a, b, a, b and c, one of A and B is oxo and the other is of the formula -P[Y] ₃ Z (in the formula,
Y is aryl and Z is an anion of an inorganic or organic acid) or a triarylphosphonium of the formula

Dialkoxyphosphinyl represented by the formula: (wherein X is alkoxy), R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , _R9 ,
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ have the same meanings as shown in the formula]. The aryl group represented by Y in the triarylphosphonium group used in the process of the invention includes all known aryl groups, but preferably monomer groups such as phenyl, lower alkyl-phenyl or lower alkoxy-phenyl. Includes nuclear aryl groups such as tolyl, xylyl, mesityl and p-methoxyphenyl. Among the inorganic acid anions represented by Z in the triarylphosphonium group used in the present invention, chloride ions, bromide ions, iodide ions, or hydrosulfate ions are preferred. A preferred organic acid anion is toxyloxy ion. The alkoxy group represented by X in the dialkoxyphosphinyl group used in the process of the invention is preferably a lower alkoxy group having 1 to 6 carbon atoms, particularly preferably a methoxy and ethoxy group. Compounds within the formula, some of which are new, include, for example, the substituted benzaldehyde obtained by treating suitably substituted benzene with a formylating agent in the presence of a Lewis acid in a conventional manner. It can be produced by condensing with acetone according to a conventional method. Obtained 4-
(Substituted phenyl)-but-3-en-2-one (
a) is then condensed with (diethoxyphosphinyl)acetic acid ethyl ester or with (diethoxyphosphinyl)fluoroacetic ester according to conventional methods to give 3-methyl-5-(substituted phenyl)- It is changed to penta-2,4-dien-1-oitsucic acid ethyl ester or 2-fluoro-3-methyl-5-(substituted phenyl)-penta-2,4-dien-1-oitsucic acid ethyl ester. The obtained carboxylic acid ester was treated with diisobutylaluminum hydride or bis-(2-methoxy-
ethoxy) sodium aluminum hydride in a conventional manner. The resulting 3-methyl-5-(substituted phenyl)-penta-2,4-dien-1-ol or 2-fluoro-3-methyl-5-(substituted phenyl)-penta-2,4-dien-1- Treatment of the ol with an oxidizing agent such as manganese dioxide in an organic solvent such as acetone or methylene chloride provides compounds within formula a where A is an oxo group. Compounds of formula a in which A is a triarylphosphonium group or a dialkoxyphosphinyl group are 3-methyl-5-(substituted phenyl)-penta-2,4-dien-1-ol or 2- Fluoro-3-methyl-5-(substituted phenyl)-penta-2,4-dien-1-ol is halogenated by treating it with phosphorus trihalide or phosphorus pentahalide according to a conventional method, and the resulting halide is obtained. can be produced by reacting with triarylphosphine or trialkyl phosphite. Formula a having a trifluoromethyl group on the side chain
Compounds within the scope of are prepared, for example, by treating a suitably substituted benzaldehyde with a propangyl-Grindard reagent (i.e. CF ₃ C≡C-MgBr) and subjecting the resulting propargyl compound to a Meyer-Schüster rearrangement reaction (Meyer-Schüster rearrangement) in an acidic medium. Schuster
It can be produced by rearrangement reaction by treatment with mercuric sulfate. Compounds within the scope of formula a are also compounds of formula b
Formula the compound of [wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in the formula and A is as defined in the formula] I can do it. When A is oxo, the starting material of formula is reacted with a compound of formula where B is either triarylphosphonium or dialkoxyphosphinyl as in formula to form a new formula [In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₈ , R ₁₀ , R ₁₁
and R ₁₄ are the same as in formula and, except that the new intermediate compound does not necessarily have fluorine or trifluoromethyl, so the proviso to the formula is omitted. When B in formula b is oxo, A in formula
is triarylphosphonium or dialkoxyphosphinyl. The preparation of compounds of formula b is described in the literature. Reaction of compounds represented by formulas a, b and c with compounds represented by formulas a, b and c yields compounds represented by formulas. The reaction is the Wittig reaction or the Horner reaction.
reaction). According to the Uittich method, the respective starting materials are combined in the presence of an acid binder (for example an alkali metal alcoholate such as sodium methylate or an optionally alkyl-substituted alkylene oxide, preferably ethylene oxide or 1,2-butylene oxide). The reaction is carried out in a solvent (for example a chlorinated hydrocarbon such as methylene chloride or dimethylformamide) or without a solvent at room temperature to the boiling point of the reaction mixture. According to the Horner method, the reaction is carried out with a base, preferably in the presence of an inert organic solvent, for example with sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. Alternatively, it is carried out using an alkali metal alcoholate in an alkanol (for example using sodium methylate in methanol) at a temperature from 0° C. to the boiling point of the reaction mixture. The carboxylic acids of the formula can be converted to acid chlorides in conventional manner, for example by treatment with thionyl chloride, preferably in pyridine, which acid chlorides can then be converted to esters by reaction with alkanols or to esters by reaction with ammonia. can be converted to amide. The carboxylic acid ester represented by the formula is hydrolyzed in a conventional manner, for example by treatment with an alkali, especially water-alcoholic sodium hydroxide or potassium hydroxide, at room temperature to the boiling point of the mixture. It can be done. The resulting carboxylic acid can then be amidated via an acid halide as described above. Further, carboxylic acid esters can also be directly amidated as described later. The carboxylic ester of the formula can be converted directly to the reactive amide by treatment with lithium amide. This treatment can advantageously be carried out at room temperature. The carboxylic acid or carboxylic ester represented by the formula can be reduced to the reaction alcohol represented by the formula by conventional methods. This reduction is advantageously carried out using metal hydrides or alkyl metal hydrides in an inert solvent. Examples of hydrides that have been found to be particularly suitable are mixed metal hydrides such as lithium aluminum hydride or bis-(2-methoxy-
ethoxy)-sodium aluminum hydride. Suitable inert solvents are in particular ether, tetrahydrofuran or dioxane when lithium aluminum hydride is used and ether when diisobutylaluminum hydride or bis-(2-methoxy-ethoxy)-sodium aluminum hydride is used. , hexane, benzene or toluene. Alcohols of the formula can be prepared, for example, by iodination, in an organic solvent such as dioxane, tetrahydrofuran, 1-2-dimethoxyethane or dimethylformamide, in the presence of a base, preferably sodium hydride, at a temperature of 0 DEG C. to room temperature. It can be etherified with an alkyl halide such as ethyl. Alcohols of the formula can be esterified by treatment with an alkanoyl halide or anhydride, conveniently in the presence of a base such as pyridine or triethylamine, at room temperature to the boiling point of the mixture. The alcohol ester obtained above can be saponified by conventional methods, such as those described above in connection with the saponification of carboxylic acid esters. The acetal obtained above is treated with a proton donor in an inert solvent according to conventional methods (e.g. using hydrochloric acid in tetrahydrofuran).
Can be hydrolyzed. The alcohol represented by the formula or its ester can be oxidized according to conventional methods to give the carboxylic acid of the reaction represented by the formula. This oxidation is advantageously carried out using silver oxide () and an alkali in water or a water-miscible organic solvent at a temperature between room temperature and the boiling point of the oxidizing mixture. The carboxylic acids of the formula form salts with bases, especially alkali metal hydroxides, especially sodium hydroxide 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 4-(diethoxyphosphinyl)-2(Z,E)-fluoro- in 10 ml of 1,2-dimethoxyethane
3-Methyl-crotonic acid ethyl ester 5.05g
(0.0179 mol), 1,2-dimethoxyethane 50
Sodium hydride (50% dispersion in oil) 0.83 in ml
(0.0173 mol) (washed with pentane to remove oil) was added dropwise to a cold (0-5° C.) suspension.
The resulting mixture was stirred at 23°C for 1.0 hour. This dark brown mixture was then diluted with 5-(4-methoxy-2,3,6-
Trimethylphenyl)-3-methyl-2(E),4(E)
4.35 g (0.0178 mol) of -pentadiene-1-al was added. The resulting reaction mixture was stirred at 23° C. under argon for 2.0 hours. Next, add this to 250 ml of ice water.
ml, acidified to PH4 with 1N hydrochloric acid, and extracted with methylene chloride (3 x 200 ml). Combine this methylene chloride extract with water (2 x 200ml)
and saturated brine (2 x 150ml) and dried over magnesium sulfate. Evaporation of the solvent to dryness under reduced pressure gave a crude crystalline product, which was purified by column chromatography on 250 g of silica gel. Ether - petroleum ether (5:
Elution with 95) gives a crystalline product, which is recrystallized from methylene chloride-petroleum ether to give pure 9-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3, 7-dimethyl-
2(Z),4(E),6(E),8(E)-nonatetraenoic acid ethyl ester was obtained as yellow crystals with a melting point of 140-143°C. Example 2 9-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3,7-dimethyl-2(Z),4(E),6(Z),8(E) -nonatetraenoic acid ethyl ester 4-(diethoxyphosphinyl)-2(Z,E)-fluoro- in 10 ml of 1,2-dimethoxyethane
3-Methylcrotonic acid ethyl ester 5.52g
(0.0196 mol), 1,2-dimethoxyethane 50
Sodium hydride (50% dispersion in oil) in ml
0.984 g (0.0205 mol) (washed with pentane to remove oil) was added dropwise to a cold (0-5° C.) suspension. The resulting mixture was stirred at 23°C for 1.0 hour.
Then 5- in 20 ml of 1,2-dimethoxyethane
4.80 g (0.0196 mol) of (4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(Z),4(E)-pentadien-1-al was obtained as a dark brown suspension. added to. The resulting reaction mixture was heated to 23°C.
Stir under argon for 2.0 h, then add 250 ml of ice water.
I poured it inside. Work-up as described in Example 1 gave a crude oily product which was quickly chromatographed on 250 g of silica gel. Elution with ether-petroleum ether (5:95) gave an oil which was further purified by recrystallization five times from petroleum ether to yield 9-(4-methoxy-2,3,6-trimethylphenyl). )-2-
Fluoro-3,7-dimethyl-2(Z),4(E),
6(Z),8(E)-nonatetraenoic acid ethyl ester was obtained as yellow crystals with a melting point of 103-113°C.
High pressure liquid chromatography analysis of this substance is approximately 90%
It showed purity. 5- used as starting material in Example 1
(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(E),4(E)-pentadiene-
1-al and 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(Z),4(E) used as starting material in Example 2.
-Pentadiene-1-al could be produced, for example, as follows. a 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(Z,E),4(E)
- Preparation of pentadienoic acid methyl ester 4.92 g of sodium hydride (50% dispersion in oil, 0.103 mol) washed with 3 x 50 ml of pentane was added to 1.0
I put it in a three-necked round-bottomed flask. 330 ml of 1,2-dimethoxyethane (distilled over lithium aluminum hydride) are added and the mixture is cooled to 0°C and 20.08 g of (dimethoxyphosphinyl)acetic acid methyl ester
(0.111 mol) was slowly added. The resulting mixture was warmed to 23 °C and placed under argon at this temperature.
Stir mechanically for 2.0 hours. Add 50 ml of 1,2-dimethoxyethane to the resulting thick white paste.
20.0 g of 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one in
(0.092 mol) was added dropwise. The resulting mixture 23
Stirred at °C for 45 minutes, then refluxed for 2.5 hours. It was then cooled in an ice bath and the contents poured in portions onto 1.2 ml of ice water. The resulting solution was then neutralized to pH 6-7 with 2N hydrochloric acid, followed by extraction with methylene chloride (3x300ml). Combine the methylene chloride extracts and add water (3x
200ml) and brine (1 x 300ml) and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave an orange-yellow oil which was quickly chromatographed on 250 g of silica gel. Elution with chloroform yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(Z,E),4
(E)-Pentadienoic acid methyl ester was given as a pale orange oil. The ratio of isomers was approximately 2:3 (2Z:2E) as determined by NMR analysis. b 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(Z,E),4(E)
- Preparation of pentadien-1-ol 5-(4-methoxy-
40.0 g (0.146 mol) of 2,3,6-trimethylphenyl)-3-methyl-2(Z,E),4(E)-pentadienoic acid methyl ester was placed in a 2.0 volume three-neck round bottom flask. The solution was cooled to -73°C and under argon 106 ml of diisobutylaluminum hydride (1.5 mol in hexane,
0.160 mol) was added. The resulting reaction mixture was stirred at -73°C for 30 minutes and examined by thin layer chromatography. Furthermore, diisobutylaluminum hydride (100 ml, 0.15 mol) was added again every 30 minutes in three portions while stirring at -73°C. Thin layer chromatography showed that only traces of starting material were present.
The reaction mixture was gradually warmed to -30°C and 250 ml of methanol-water (1:1) was slowly added under stirring. Water (500ml) was then slowly added and the temperature maintained at approximately 10°C until precipitation ceased. The mixture was filtered through Celite and washed several times with ether. Separate the ether phase
1N hydrochloric acid (3x100ml) and saturated brine (3x
100ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure yielded 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(Z,E),4
(E)-Pentadien-1-ol was obtained as a yellow oil. Analytical samples showed the isomer ratio of 2E and 2Z to be approximately 2:1. c 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(E),4(E)-pentadien-1-al and 5-(4-methoxy-2,3, 6-trimethylphenyl)-3-
Methyl-2(Z),4(E)-pentadiene-1-
Preparation of Earl 306 g (3.5 moles) of manganese dioxide and 750 ml of methylene chloride were placed in a 2.0 volume three-neck round bottom flask. The flask was flushed with argon. To the above well-stirred mixture was added 5-(4-methoxy-2,
3,6-trimethylphenyl)-3-methyl-
66 g (0.268 mol) of 2(Z,E),4(E)-pentadien-1-ol was added. The resulting mixture was mechanically stirred at 23°C under argon for 4 days.
The resulting mixture was filtered over Celite and the filter cake was washed with 2.0 methylene chloride.
The solvent was evaporated under reduced pressure to give a crude oil.
This material was purified first by column chromatography on silica gel (800 g) and then by preparative high pressure chromatography. This procedure yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(Z),4(E)
-Pentadien-1-al was isolated as the less polar component, which upon recrystallization from ether-petroleum ether gave pale yellow crystals with a melting point of 82-85°C. Further elution of the column yielded 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2(E),4(E)-pentadien-1-al with a melting point of 61-63°C ( Obtained as pale yellow crystals (recrystallized from ether-petroleum ether). 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 (50% dispersion in oil, 0.024 mole) of sodium hydride was placed in a 250.0 ml three-necked flask and washed with 2 x 50 ml pentane.
25 ml of 1,2-dimethoxyethane (distilled from lithium aluminum hydride) was added.
Add 25 ml of 1,2-dimethoxyethane to this mixture.
4-(dimethoxyphosphinyl)-3-methyl-crotonic acid methyl ester 5.328 g (0.024
mol) was added dropwise over 20 minutes under argon with mechanical stirring. The resulting mixture was stirred for an additional 2.0 hours at 23°C under argon. To this dark brown solution was added 5-[4-methoxy-2,3,6-trimethylphenyl]-2-fluoro-3-methyl-2 in 55 ml of 1,2-dimethoxyethane.
(Z),4(E)-Pentadiene-1-R6.288
g (0.024 mol) was added dropwise over 35 minutes. A dark brown syrup formed. Add this mixture again to 23
Stirred at °C under argon for 2.5 hours. Cool this in an ice bath and add ice water (500ml).
The solution was then neutralized with 1N hydrochloric acid to a pH of 5-6. Methylene chloride (200ml) was added and stirring continued for several minutes. The layers were separated and the aqueous layer was further extracted with methylene chloride (3x200ml).
Combine the methylene chloride extracts and add water (3 x 100ml)
and dried over anhydrous magnesium sulfate. The solvent was removed on a rotary evaporator at 40° C./30 mm Hg to obtain the crude product;
This was chromatographed on 300 g of silica gel and ether-petroleum ether (1:9)
(30-60°C) to obtain a yellow-orange crystalline substance. Fractional crystallization of this yellow-orange crystalline material from methylene chloride-petroleum ether (1:4) or acetone yields pure 9-(4-methoxy-
2,3,6-trimethylphenyl)-6-fluoro-3,7-dimethyl-2(E),4(E),6
(Z),8(E)-nonatetraenoic acid methyl ester was obtained as yellow-orange crystals with a melting point of 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)-nonatetraene Acid methyl ester The mother liquor from Example 3 is evaporated to dryness and the resulting oily residue is crystallized from ether-petroleum ether (approx. 1:1) at 23°C to give 9-
(4-methoxy-2,3,6-trimethylphenyl)-6-fluoro-3,7-dimethyl-2
(Z),4(E),6(Z),8(E)-nonatetraenoic acid methyl ester was obtained as yellow crystals with a melting point of 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 4- in 25 ml of dry 1,2-dimethoxyethane
5.32 g (0.024 mol) of (dimethoxyphosphinyl)-3-methyl-crotonic acid methyl ester in nitrium hydride (1.152 g, 0.024 mol, 50% dispersion in oil) in 25 ml of dry 1,2-dimethoxyethane.
(washed with petroleum ether to remove oil) was added dropwise to the suspension. The resulting reaction mixture was stirred at 25° C. under argon for 1.5 hours. 5-(4-methoxy-2,
3,6-trimethylphenyl)-2-fluoro-
6.288 g (0.024 mol) of 3-methyl-2(E),4(E)-pentadien-1-al was added dropwise. The resulting reaction mixture was then stirred at 25° C. for 17 hours and refluxed under argon for 1.0 hour. It was then cooled in an ice bath. Ice water (500ml) was added and the resulting solution was acidified with 1N aqueous hydrochloric acid to a pH of about 3-4. This was then diluted with methylene chloride (3x
200ml). The methylene chloride extracts were combined, washed with water (3 x 100 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to give an orange crystalline material that was purified by chromatography on 200 g of silica gel. . Elution with 5-10% ether in petroleum ether gave yellow crystals which were dissolved in methylene chloride-petroleum ether (1:
When recrystallized twice from 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 has a melting point of 133
Obtained as yellow needles at ~141°C. An analytical sample was obtained by recrystallizing the above material once more, melting point 139-143°C. 5- used as starting material in Example 3
(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3-methyl-2(Z),4(E)
-pentadien-1-al and 5-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3-methyl-2(E),4(E) used as starting material in Example 4. )-pentadiene-
1-R could be produced, for example, as follows. a Production of 5-[4-methoxy-2,3,6-trimethylphenyl]-2(Z,E)-fluoro-3-methyl-2,4(E)-pentadienoic acid ethyl ester Sodium hydride 14.4g (50% dispersion in oil,
0.30 mol) in a 2.0 volume three-necked flask under argon and washed with 100 ml of pentane. Then 1,2-dimethoxyethane (250
ml, distilled from lithium aluminum hydride) was added and the flask was allowed to cool in an ice bath. The resulting mixture was stirred well and 72.7 g (0.30 mol) of (diethoxyphosphinyl)-fluoroacetic acid ethyl ester in 80 ml of 1,2-dimethoxyethane were added dropwise under argon over a period of 30 minutes. The resulting mixture was again stirred at 23° C. under argon for another 2 hours and the color became brown. Furthermore, 1,2-dimethoxyethane (70
ml) was added. Then under vigorous stirring 1,
4-(4-methoxy-2,3,6-trimethylphenyl)-3 in 200 ml of 2-dimethoxyethane
-buten-2-one 65.4g (0.30mol) at 23℃
The mixture was added dropwise over 40 minutes. An exothermic reaction was observed and a brown syrupy precipitate began to appear. The reaction was heated for an additional 1.0 h at 23°C and
Stirred at 52-55°C for 4.0 hours. The flask was cooled in an ice bath, ice water (1.0) was added, the solution was adjusted to PH 4-5 with 1N hydrochloric acid, and extracted with methylene chloride (3 x 250ml). The methylene chloride extracts were combined, washed with water (3 x 200ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness under reduced pressure on a rotary evaporator to give a brown oil, which was purified by column chromatography on 800 g of silica gel. Elution with ether-petroleum ether (5:95) (30-60°C) yielded pure 5-[4-methoxy-2,3,6-trimethylphenyl]-2(Z,E)-fluoro-3. -Methyl-2,4(E)-pentadienoic acid ethyl ester was obtained as an isomer mixture with a ratio of approximately 2(Z):2(E)=3:2. b Production of 5-[4-methoxy-2,3,6-trimethylphenyl]-2(Z,E)-fluoro-3-methyl-2,4(E)-pentadien-1-ol 5-[4 -methoxy-2,3,6-trimethylphenyl]-2(Z,E)-fluoro-3-methyl-2,4(E)-pentadienoic acid ethyl ester (57.5 g (0.188 mol)) was dissolved in anhydrous ether (1.20
) and cooled to −70° C. in a dry ice-acetone bath under argon with stirring. (crystallization occurred). Diisobutylaluminum hydride (250 ml, 1.5 mol in hexane) was then added to an internal temperature of -65°C to -70°C.
The addition was carried out dropwise over 30 minutes at a rate such that . The reaction was monitored by thin layer chromatography which showed the presence of the starting ester. Then, further diisobutylaluminum hydride (125
ml) was added over 2.0 hours and thin layer chromatography showed no more starting material was present. Methanol/water (1:1, 50 ml) was slowly added and the reaction mixture was heated to temperature 5 for several minutes.
Stirring at ˜10° C. stopped forming a precipitate in an exothermic reaction. The precipitate was filtered through Celite and washed with ether (4 x 800ml). The liquids were combined (approximately 4.5 cm), transferred to a separatory funnel, and the layers were separated. The aqueous phase was further extracted with 500 ml of ether. The ether extracts were combined, washed with water (3 x 800ml) and dried over anhydrous magnesium sulfate. Evaporation of the ether to dryness on a rotary evaporator afforded the crude material, which was crystallized from ether-petroleum ether (~1:30) (30-60°C) to yield 5-[4-methoxy-2,3 ,6-trimethylphenyl]-2(Z,E)-fluoro-3-methyl-2,4(E)-pentadien-1-ol is obtained as yellow crystals with a melting point of 48-80°C. c 5-[4-methoxy-2,3,6-trimethylphenyl]-2-fluoro-3-methyl-2
(Z),4(E)-pentadien-1-al and 5-[4-methoxy-2,3,6-trimethylphenyl]-2-fluoro-3-methyl-2
Production of (E),4(F)-pentadien-1-al 5-[4-methoxy-2,3,6-trimethylphenyl]-2(Z,E)-fluoro-3-methyl-2,4 (E)-Pentadien-1-ol
53.5 g were dissolved in 300 ml of methylene chloride and added in portions under argon to a mechanically stirred mixer of manganese dioxide (200 g) in 800 ml of methylene chloride. The mixture was stirred in the dark for 3 days. More manganese dioxide (100 g) was added and stirring continued under argon for a further 4 days. The mixture was filtered through Celite and the percake was washed well with methylene chloride (approximately 1.5).
The solvent was evaporated to dryness in a rotary evaporator to give a pale brown oil, which was evaporated onto silica gel.
Chromatographed on 1.4Kg. Elution with diethyl ether-hexane (1:9) gave a crystalline product, which was recrystallized once from ether-petroleum ether (1:1) to give pure 5
-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3-methyl-2(E),
4(E)-pentadiene-1-al has a melting point of 79-84
Obtained as pale yellow crystals at ℃. Further elution of Kamura with diethyl ether-hexane (1:4) yielded 5-(4-methoxy-2,3,6
-trimethylphenyl)-2-fluoro-3-
Methyl-2(Z),4(E)-pentadiene-1-
R was obtained as pale yellow crystals with a melting point of 87-91°C. The analyzed sample had a melting point of 89-93°C after being recrystallized twice from ether. 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-(diethoxyphosphinyl)-4-fluoro-3- in 20 ml of 1,2-dimethoxyethane
Methyl-crotonic acid ethyl ester 4.88g
(0.0178 mol) in 1.25 g of sodium hydride in 60 ml of dry 1,2-dimethoxyethane (distilled from lithium aluminum hydride)
(0.025 mol, 50% dispersion in oil) (washed with petroleum ether to remove oil) was added dropwise under argon at 23°C. The resulting mixture was heated to 23°C.
for 10 minutes and then refluxed for 1.25 hours with stirring under argon. This was then cooled to 35-40°C over 1 hour and the resulting light brown reaction mixture was treated with 5-(4-methoxy-2,3,6-trimethylphenyl) in 20 ml of 1,2-dimethoxyethane. )-3-methyl-2(E),4(E)-pentadien-1-al 4.23g (0.0173mol)
It was added dropwise over 30 minutes. The resulting reaction mixture
Stir for 1.5 h at 23 °C, then 45 h under argon.
Reflux for minutes. It was then cooled in an ice bath and approximately 400 ml of crushed ice water was added. The resulting solution was then adjusted to pH 2 with 1N aqueous hydrochloric acid. Methylene chloride (250ml) was added and the resulting mixture was stirred for approximately 10 minutes. The aqueous phase was then separated from the methylene chloride phase and further extracted with methylene chloride (3 x 150ml). The methylene chloride extracts were combined, washed with water (2 x 100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a brown oil, which was column chromatographed on silica gel (700 g). Purified by E. When eluted with 5% ether in petroleum ether, yellow crystals of 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 obtained as a less polar isomer with a melting point of 76-83°C, which when recrystallized from petroleum ether has a melting point of Pure material was obtained at 78-84°C. Further elution of the column with 5-10% ether in petroleum ether gave the more polar isomer, mp 84-93°C, which was recrystallized from ether to give pure 9-(4-methoxy-2 ,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2(E),4(Z),
6(E),8(E)-nonatetraenoic acid ethyl ester was obtained as yellow crystals with a melting point of 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 745 mg (3.35 mmol) of 4-(dimethoxyphosphinyl)-3-methyl-crotonic acid methyl ester in 5 ml of 1,2-dimethoxyethane are dissolved in dry 1,2-dimethoxyethane (5 ml). Added at 0° C. to a suspension of 116 mg (3.35 mmol) of sodium hydride (50% dispersion in oil, oil removed by three washes with pentane). The resulting mixture was first heated to 0°C.
Stirred for 10 minutes at 23°C and then 1 hour under argon at 23°C. The above mixture was then added with 5-(4-methoxy-
2,3,6-trimethylphenyl)-3-trifluoromethyl-2(E),4(E)-pentadiene-1-
1.0 g (3.35 mmol) of Earl was added over 15 minutes. The resulting reaction mixture was stirred at 23° C. for 3 hours and refluxed for an additional 30 minutes. This was cooled in an ice bath and (250ml) was added. The solution was adjusted to pH 4 with 1N aqueous hydrochloric acid, then diluted with methylene chloride (4
×50ml). The methylene chloride extracts were combined, washed with water and brine and dried over magnesium sulfate. Evaporation of the methylene chloride under reduced pressure gave the crude product, which was purified by column chromatography on 25 g of silica gel. Elution with 5% ether in petroleum ether gives 5-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-2(E),
4(E)-pentadien-1-al was obtained. Further elution with 5% ether in petroleum ether increases the melting point when recrystallized from petroleum ether.
9-(4-methoxy-2,3,6-trimethylphenyl)-3 as yellow crystals with a temperature of 112-113.5°C.
-Methyl-7-trifluoromethyl-2(E),4
(E),6(E)-nonatetraenoic acid methyl ester was obtained. 5- used as starting material in Example 6
(4-Methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-2(E),4(E)-pentadien-1-al could be produced, for example, as follows. . a 4-(4-methoxy-2,3,6-trimethylphenyl)-1,1,1-trifluoro-2
-Preparation of butyn-4-ol 43.3 g (0.40 mol) of ethyl bromide was mixed with 10.6 g of metallic magnesium in 1.0 mol of dry ether.
(0.436 mol) was added dropwise to the refluxing mixture under argon over a period of 1 hour. The resulting reaction mixture was refluxed for a further 1.5 h under stirring and then
Cooled to 23°C. To this mixture of ethylmagnesium bromide was added trifluoropropyne (41.0 g, 0.436 mol) through a gas dispersion tube. The resulting reaction mixture was stirred at 23° C. under argon while trifluoropropyne was circulated three times. A brown viscous oil of trifluoropropynylmagnesium bromide formed. Add 50 g of 2,3,6-trimethyl-4-methoxy-benzaldehyde to this mixture.
(0.281 mol) was added over 30 minutes with vigorous stirring at 23° C. under argon. This is 23
Stirred for an additional 2 hours at ~30°C. Additionally 2,3,6-trimethyl-4 in ether (100 ml)
-Methoxy-benzaldehyde (10g, 0.056
mol) was added and the reaction was stirred for an additional hour. The mixture was cooled in an ice bath and a saturated aqueous solution of ammonium chloride was slowly added with stirring. The layers were separated and the aqueous phase was extracted three times with ether. Combine the ether extracts,
Washed with water and dried over anhydrous magnesium sulfate. Evaporation of the ether to dryness under reduced pressure afforded the crude product, which was recrystallized twice from chloroform-hexane to give 4-(4-methoxy-2,3,6-trimethylphenyl)-1,
1,1-trifluoro-2-butyn-4-ol was obtained as white crystals with a melting point of 126-130°C. The analytical sample melted at 127-129.5°C. b 4-(4-methoxy-2,3,6-trimethylphenyl)-1,1,1-trifluoro-3
Preparation of (E)-buten-2-one 92 mg (0.233 mmol) of mercuric sulfate in 5 ml of acetic acid and 0.05 ml of concentrated sulfuric acid are combined with 4-(4-methoxy-2,3,6-trimethyl phenyl)-1,1,1-trifluoro-2-
Added to a solution of 277 mg (1.02 mmol) of butyn-4-ol. The resulting mixture was refluxed for 2 hours while stirring. This was then diluted with 150 ml of ice water and extracted with ether (3 x 40 ml). The ether extracts were combined, washed with water and dried over anhydrous magnesium sulfate. Remove the solvent under reduced pressure (45
Evaporation to dryness at ~50°C/20 mmHg) gave a yellow crystalline product, which was recrystallized twice from petroleum ether to give 4-(4-methoxy-2,3,
6-Trimethylphenyl)-1,1,1-trifluoro-3(E)-buten-2-one has a melting point of 79~
Obtained as yellow crystals at 82°C. Similarly, this crystalline material is 4-(4-methoxy-2,3,6-trimethylphenyl)-1,
It was also prepared from 60 g of 1,1-trifluoro-2-butyn-4-ol. c 5-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-2
Preparation of (E),4(E)-pentadienoic acid methyl ester (dimethoxyphosphinyl)-acetic acid methyl ester in 50 ml of 1,2-dimethoxyethane 20.08
g (0.111 mol) in a suspension of 4.92 g (0.103 mol, 50% dispersion in oil) of sodium hydride (washed free of oil with pentane) in 200 ml of 1,2-dimethoxyethane. Added dropwise at °C. The resulting mixture was stirred at 23°C under argon for 2 hours. The resulting white pasty mixture was then treated with 4-(4-methoxy-2,3,6-trimethylphenyl)1,1,1-trifluoro-3(E) in 200 ml of 1,2-dimethoxyethane. )−
25 g of buten-2-one were added dropwise. The resulting reaction mixture was stirred at 23° C. for 30 minutes and then refluxed for 2 hours. This was then cooled in an ice bath,
The contents were then poured into ice water 1.0.
The resulting solution was neutralized to pH 7 with 2N aqueous hydrochloric acid and then extracted with methylene chloride (3 x 200ml). The methylene chloride extracts were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. Evaporation of the methylene chloride solution to dryness under reduced pressure gave the crude product, which was purified by column chromatography on silica gel (700 g). Elution with 3% ether in petroleum ether yields 5-(4-methoxy-2,
3,6-Trimethylphenyl)-3-trifluoromethyl-2(E),4(E)-pentadienoic acid methyl ester is obtained which, when crystallized from pentane at -72°C, has a melting point of 42-48°C. Yellow crystals were obtained. d 5-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-2
Production of (E),4(E)-pentadien-1-ol Diisobutylaluminum hydride 69.5ml
(1.53 mol, 0.106 mol in hexane) of 5-(4-methoxy-2,3,
A solution of 17.44 g (0.0531 mol) of methyl pentadienoic acid (6-trimethylphenyl)-3-trifluoromethyl-2(E),4(E) at -72°C.
was added dropwise over 30 minutes. The resulting solution is −72
Stirred for 20 minutes at °C under argon. Furthermore, diisobutylaluminum hydride (25ml.
38.25 mmol) and the reaction mixture -
Stirred for an additional 30 minutes at 72°C. Then methanol-water (1:1) was added to the resulting yellow solution.
100ml was added under stirring at -72°C. The resulting mixture was stirred and slowly warmed to 23°C. The precipitate formed was removed by filtration and washed well with ether. The liquid ether phase was separated, washed with water and brine and dried over magnesium sulfate. The ether solution was evaporated to dryness under reduced pressure to give a yellow crude crystalline product, which was recrystallized from petroleum ether to give 5
-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-2(E),4
(E)-Pentadien-1-ol, melting point 69-71
℃ was obtained. e 5-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-2
Preparation of (E),4(E)-pentadien-1-al Manganese dioxide (78 g, 0.896 mol) and 5-(4-methoxy-2,3,6-trimethylphenyl) in dry methylene chloride (750 ml) -3
A mixture of -trifluoromethyl-2(E),4(E)-pentadien-1-ol (13 g, 0.0434 mol) was stirred at 23° C. under argon for 15 hours. The resulting mixture was filtered through Celite and the precipitate was washed thoroughly with methylene chloride (1.0 total). The methylene chloride was evaporated to dryness under reduced pressure to give an oily crude product, which was purified by column chromatography on 600 g of silica gel. Elution with 5% ether in petroleum ether yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-
2(E),4(E)-pentadien-1-al was obtained as a yellow oil. The analytical sample was obtained as yellow crystals by crystallization from pentane,
Melting point 55-58℃. Example 7 9-(4-methoxy-2,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2(E),4(Z),6(E),8(E) - Nonatetraenoic acid methyl ester 2.37g of sodium hydride 50% dispersion in oil
(0.0494 mol) was placed in a flame-dried 500 ml three-necked flask under argon and then washed three times with 10 ml of pentane to remove the oil. After adding 10 ml of dry dimethoxyethane [di(methoxymethylenemethoxy)-distilled from sodium aluminum halide] (diethoxyphosphinyl)-acetic acid ethyl ester in 30 ml of dry dimethoxyethane 11.08
g (0.0494 mol) was added dropwise at 23°C with stirring. The reaction mixture was stirred at 23°C until no more hydrogen evolved (~1 hour). The resulting brown mixture was then treated with 8-(4) in 75 ml of dimethoxymethane.
-methoxy-2,3,6-trimethylphenyl)
3-Fluoro-6-methyl-3(Z),5(E),7
10 g (0.033 mol) of (E)-octatrien-2-one were added dropwise at 23 DEG C. and with stirring under argon. After the addition was complete, the reaction mixture was stirred at 23°C for 30 minutes and then at 50°C for 2.0 hours under argon. Thin layer chromatography (silica gel, ethyl acetate-hexane 15:85) showed that starting material was no longer present. The reaction mixture was then cooled to ~20 °C and 200 ml of cold water containing crushed ice.
poured on top. The resulting mixture was acidified to PH4 by dropwise addition of concentrated hydrochloric acid under stirring. The reaction was then extracted three times with 200 ml of ether. The ether extracts were combined, washed three times with 200 ml of water, and dried over anhydrous magnesium sulfate. After evaporating the ether to dryness, the resulting crude product was quickly passed through 200 g of Florisil and diluted with 10% ether.
Eluted with petroleum ether. Collect the eluate, ~40
Concentrate to near dryness under aspirator vacuum at °C. The resulting residue was added to 300 ml of methylene chloride and dissolved in Norit A10 on a steam bath.
g for ~2 minutes, then filtered and washed with 400 ml of methylene chloride. methylene chloride
Evaporation to dryness at 35-40°C/20-30mm produced a yellow crystalline substance. The crystalline material was dissolved in 25 ml of ether containing 1 ml of methylene chloride and further diluted with 50 ml of petroleum ether (30-60°C). When the resulting solution was kept at 23°C for several hours, crystallization occurred. After further cooling to 0-4°C for 18 hours, the crystals were collected, washed with 50 ml of petroleum ether and dried to give pure 9-(4-methoxy-2,
3,6-trimethylphenyl)-4-fluoro-
3,7-dimethyl-2(E), 4(Z), 6(E), 8(E)
-nonatetraenoic acid ethyl ester was obtained. 8- used as starting material in Example 7
(4-methoxy-2,3,6-trimethylphenyl)-3-fluoro-6-methyl-3(Z),5
(E),7(E)-octatrien-2-one could be produced, for example, as follows. a 7-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl-2
Production of (Z,E),4(E),6(E)-heptatrienoic acid ethyl ester 50% sodium hydride 20.16g (0.42mol)
was placed in a three-neck flask under argon and washed three times with 50 ml portions of pentane. The flask was then charged with 250 ml of dry dimethoxyethane. To the resulting mixture was added 79.92 g of (diethoxyphosphinyl)-fluoro-acetic acid ethyl ester.
(0.33 mol) was added dropwise over 30 minutes at 23° C. with stirring. The reaction was further heated at 40°C under argon for 1
Stir and heat for an hour then cool to room temperature. The resulting yellow-orange mixture was mixed with 5-(4-methoxy-2,3,
6-trimethylphenyl)-3-methyl-2
(E),4(E)-pentadiene-1-al 75g
(0.306 mol) was added dropwise with stirring under argon. The resulting reaction mixture was stirred at 23°C for 2.0 hours and at 40°C for an additional 2.0 hours. The resulting mixture was cooled to ˜20° C., poured onto 500 ml of crushed ice-water and then adjusted to pH ˜4 by adding 1N hydrochloric acid in portions with stirring. This solution was extracted four times with 500 ml of ether. The ether extracts were combined, washed four times with 500 ml of water and then 500 ml of brine and dried over anhydrous magnesium sulfate. The ether was evaporated to dryness under aspirator vacuum to give a dark orange oil which was quickly passed through 2.2Kg of silica gel. 10-20% ether by volume in petroleum ether (30-60℃)
Elution with gave the oily ester as a mixture of isomers (E:Z ~ 3:2). The column was further eluted with 40% ether to remove unreacted starting material. The resulting mixture of isomeric esters was used as is to prepare 7-(4-methoxy-2,3,6-trimethylphenyl)-
2-fluoro-5-methyl-2(Z), 4(E),
It was changed to 6(E)-heptadienoic acid ethyl ester. b 7-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl-2
Production of (Z),4(E),6(E)-heptatrienoic acid ethyl ester 7-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl-2
(Z,E),4(E),6(E)-heptatrienoic acid ethyl ester (E:Z~3:2) 66.1g (0.199
mol) was dissolved in 600 ml of dry ether and 1.4 g of iodine crystals were added portionwise to the solution. The resulting solution was stirred at 23 °C under argon for 48 h and then added with 5% sodium thiosulfate solution.
Washed three times with 200 ml and twice with 200 ml of water and dried over anhydrous magnesium sulfate. Most of the ether was evaporated under reduced pressure in a rotary evaporator to give a concentrated solution which was quickly passed through 100 g of Florisil. The column was washed with 1.5 ml of ether and the residue obtained after evaporation of the ether to dryness was then redissolved in 100 ml of ether and 600 ml of petroleum ether (30-60
diluted at ℃). The solution was kept at 23°C for 1.0 hours and at 0°C for 3.0 hours. The resulting crystals were collected, washed with cold petroleum ether, and dried to give 7-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl-2
Yellow crystals of (Z),4(E),6(E)-heptatrienoic acid ethyl ester, melting point 106-110°C, were obtained.
The mother liquor was evaporated to dryness to give an oil which was dissolved in 750 ml of ether. Add 0.83 g of iodine crystals to the resulting solution and then heat under argon at 23°C.
Stir for 70 hours and work up as described above to give 7-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl-2.
Yellow crystals of (Z),4(E),6(E)-heptatrienoic acid ethyl ester, melting point 109-111°C, were obtained. c 7-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl-2
Production of (Z),4(E),6(E)-heptatrienoic acid 150 ml of methanol and 6N sodium hydroxide
40 ml of 7-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl- dissolved in 450 ml of tetrahydrofuran.
It was added to 41.5 g (0.125 mol) of 2(Z),4(E),6(E)-heptatrienic acid ethyl ester. The resulting solution was stirred at 23°C for 15 minutes. A white precipitate formed. 500 ml of water was added to dissolve the precipitate. The resulting solution was then stirred at 23°C for 1.0 hour and most of the tetrahydrofuran and methanol were evaporated off under aspirator vacuum at 50°C. Then 150 ml of water were added and the solution was extracted twice with 200 ml of ether. The resulting alkaline aqueous phase was cooled to 0-4°C,
Acidified to pH ~3-4 with concentrated hydrochloric acid and then extracted three times with 300 ml of ether. The ether extracts were combined, washed twice with 200 ml of water and once with 200 ml of brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness under reduced pressure to give 7-(4
-methoxy-2,3,6-trimethylphenyl)-2-fluoro-5-methyl-2(Z),4
Yellow crystals of (E),6(E)-heptatrienoic acid, melting point
203-210℃ was obtained. d 8-(4-methoxy-2,3,6-trimethylphenyl)-3-fluoro-6-methyl-3
Production of (Z),5(E),7(E)-octatrien-2-one ~0.5 in a desiccator containing phosphorus pentoxide
7-(4-methoxy-2,3,6-trimethylphenyl)-2- dried at mmHg for 24 hours.
Fluoro-5-methyl)-2(Z), 4(E), 6(E)
- 37.82 g (0.124 mol) of heptadienoic acid were dissolved in 400 ml of dry tetrahydrofuran and cooled in a dry ice-acetone bath. Add methyllithium (in ether) to the resulting solution.
154 ml (0.248 mol) of 1.61 mol) were added dropwise via a syringe at -72°C under argon with stirring. After the addition was complete, the reaction mixture was stirred at −75° C. under argon for 15 minutes. Thin layer chromatography (silica gel, ethyl acetate-hexane 3:7)
showed that some acid was still present.
An additional 15.4 ml (0.025 mol) of methyllithium was then added again as before. The resulting reaction mixture was stirred at −75° C. for 1.0 hour, indicating that some acid was still present. However, no more of this reagent was added since an excess of methyllithium would lead to ter-alcohol as a by-product. The cold bath was removed and 150 ml of water was carefully added. Most of the tetrahydrofuran at 50℃/30~50mmH
It was removed with g. The aqueous solution was extracted three times with 300 ml of ether. The ether extracts were combined, washed three times with 300 ml of water and dried over anhydrous magnesium sulfate. Evaporation of the ether to dryness under reduced pressure gave the crude product, which was dissolved in 50 ml of methylene chloride.
and diluted with 300 ml of hexane. Crystallization occurred when the resulting solution was kept at 23°C for 1.0 hour. After freezing for a further 18 hours, the resulting crystals were collected, washed with 200 ml of cold hexane and dried to give an orange crystalline product, 8-(4-methoxy-2,3,6-trimethylphenyl)-3-
Fluoro-6-methyl-3(Z), 5(E), 7(E)
-octatrien-2-one, melting point 108-110
℃ was obtained. A second crop of orange product crystals, melting point 107-110°C, was obtained from the mother liquor. 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 Sodium hydride 50% dispersion in oil 1.31g
(0.027 mol) was placed in a dry flask and washed with 40 ml of petroleum ether under argon. Replace the petroleum ether with 60 ml of dry dimethoxyethane and then add 30 ml of dimethoxyethane to this resulting slurry.
6.06 g (0.027 mol) of 4-(dimethoxyphosphinyl)-3-methyl-crotonic acid methyl ester in the mixture was added dropwise with stirring. The mixture was stirred at 23°C until hydrogen evolution ceased. The resulting dark brown mixture was then treated with 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-4-fluoro-2(E) in 30 ml of dimethoxyethane,
4(Z)-pentadiene-1-al 6.0g
(0.0229 mol) was added over 10 minutes. The resulting reaction mixture was stirred at 23°C under argon for 1.6 hours, then crushed ice-water (~500ml) was slowly added. The solution was adjusted to pH ~1 with 6N hydrochloric acid and then immediately extracted with ether. This was then worked up in a conventional manner to obtain a crude product, which was subjected to column chromatography on silica gel (500
(g, 4.5 cm x 84 cm column).
Elution with 1:9 ether-petroleum ether gave a yellow crystalline material containing mainly two isomers. This yellow crystalline material was crystallized from methylene chloride/ether (1:3), resulting in 9-(4
-methoxy-2,3,6-trimethylphenyl)
-8-fluoro-3,7-dimethyl-2(E),4
(E),6(E),8(Z)-nonatetraenoic acid methyl ester was obtained as yellow crystals with a melting point of 121.5-130°C. 5- used as starting material in Example 8
(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-4-fluoro-2(E),4
For example, (Z)-pentadiene-1-al could be produced as follows. a 3-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-2(Z,E)-propenoic acid ethyl ester (diethoxyphosphinyl)-fluoro-acetic acid in 50 ml dimethoxyethane ethyl ester 60
g (0.248 mol) of dry dimethoxyethane 150
Sodium hydride 50% dispersion in oil (washed to remove oil with petroleum ether) in ml 17.8
g (0.37 mol) of the suspension at 23° C. over a period of 2.0 hours. The resulting mixture was stirred at 23°C for 3.0 hours. When hydrogen evolution was no longer observed, 2,3,6-trimethylanisaldehyde (44
g, 0.247 mol) was added over 15 minutes. The mixture was stirred at 23°C under argon for 20 hours. An additional 20 g (0.0825 mol) of (diethoxyphosphinyl)-fluoro-acetic acid ethyl ester in 20 ml of dimethoxyethane was then added in portions. The reaction mixture was stirred and refluxed under argon for 1.5 hours. After cooling the reaction mixture to ˜30° C., 1.92 g (0.04 mol) of 50% sodium hydride and 5.0 g (0.0206 mol) of (diethoxyphosphinyl)-fluoro-acetic acid ethyl ester in 10 ml of dimethoxyethane were added. . 0.5 more
After refluxing for an hour, thin layer chromatography showed that the reaction was no longer proceeding. The resulting reaction mixture was cooled to ~4°C and crushed ice-water
1.0 poured on top. The resulting solution was diluted with 150% 1N hydrochloric acid.
Acidified to PH2 by adding ml portionwise. Pour the resulting solution into 400ml of methylene chloride.
Extracted three times. Combine the methylene chloride extracts,
Washed 5 times with 500 ml of water and once with 250 ml of salt water,
It was then dried over anhydrous sodium sulfate. Evaporation of the solvent to dryness under reduced pressure gave a brown oil, which was shown by thin layer chromatography to contain approximately 90-95% product. This oil was purified by chromatography on 1.5Kg of silica gel. 1:19 to 1:9 ether/petroleum ether (30-60°C)
When eluted with 3-[4-methoxy-2,
3,6-Trimethylphenyl]-2-fluoro-2(Z,E)-propenoic acid ethyl ester was obtained as a pale yellow oil. b Production of 3-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-2(Z,E)-propene 0.586 mol) of 6N aqueous sodium hydroxide solution (97.7 ml) in 150 ml of methanol 3[4-methoxy-2,3,6-trimethylphenyl]-2-
Add dropwise to a stirred solution of 78.10 g (0.293 mol) of fluoro-2(Z,E)-propenoic acid ethyl ester. A white precipitate appeared and became very dense. The resulting mixture was stirred rapidly at 23° C. for 0.5 h and then diluted with 1.0 ml of ice water. ~50ml of concentrated hydrochloric acid was added dropwise to the well-stirred mixture until a pH of 1 was reached. The precipitated white solid was extracted three times into 400 ml of ether. The ether extracts were combined, washed once with 500 ml of brine, and dried over anhydrous sodium sulfate. When ether is evaporated to dryness under reduced pressure, the melting point
A white solid was formed at 157-184°C which was dried under high vacuum over phosphorus pentoxide at 23°C for several days to give 3-(4-methoxy-2,3,6-trimethyl)-2-fluoro-2. (Z,E)-propenoic acid, melting point 163-181°C, was obtained. c Preparation of 4-(4-methoxy-2,3,6-trimethylphenyl)-3-fluoro-3(Z)-buten-2-one 3-(4- Methoxy-2,3,
6-trimethylphenyl)-2-fluoro-2
A solution containing 25 g (0.105 mol) of (Z,E)-propenoic acid was heated at -70°C in a dry ice-acetone bath.
It was cooled to To this cooled solution was then added 47.5 ml of methyllithium (0.105 mol, in ether).
2.23 mol) was slowly injected from a hypodermic syringe under argonization with stirring at a rate such that the internal temperature was maintained between -60 and -70°C. The mixture was stirred at -70°C under argon for 10 minutes. An additional 47.5 ml of methyllithium was then similarly injected into the solution. The resulting solution was stirred at −70° C. for 1.0 h under argonization. An additional 5 ml (0.0115 mol) of methyllithium was added as before and stirring continued for 10 minutes. The resulting reaction mixture was then carefully poured onto 500 ml of crushed ice water, acidified to pH ~1.0 with concentrated hydrochloric acid, and extracted with ether. This was separated into a neutral fraction and an acidic fraction, and the crude product 4-[4-methoxy-2,3,6-trimethylphenyl]-3-
Fluoro-3(Z)-buten-2-one was obtained as a pale yellow oil and a small amount of unchanged starting material as a white solid. The crude product was then purified by column chromatography on 1.6 Kg of silica gel (8.6 x 86 cm column). 1:9
Elution with ether-petroleum ether gave a low melting point crystalline material. Further elution with 1:9 ether/petroleum ether isolated the crystalline E-isomeric ketone compound, mp 56-59°C. Further elution with the same eluent yielded the Z-isomer, which was purified using petroleum ether (30-60°C).
When crystallized from 4-(4-methoxy-2,
3,6-Trimethylphenyl)-3-fluoro-3(Z)-buten-2-one, melting point 34-43.5
℃ was obtained. d 5-[4-methoxy-2,3,6-trimethylphenyl]-3-methyl-4-fluoro-
Preparation of (diethoxyphosphinyl)-acetic acid ethyl ester 26.84 g (0.12 mol) of 5.75% (0.12 mol) of sodium hydride 50 in oil in 200 ml of dry dimethoxyethane. mol) (which was washed with petroleum ether to remove the oil) over a period of 25 minutes. The mixture was stirred at 23 °C for 1.0 h;
Then unsaturated 4-
[4-Methoxy-2,3,6-trimethylphenyl]-3-fluoro-3(Z)-butene-2-
23.53 g (0.0997 mol) of ion was added dropwise. The reaction mixture was stirred at 23° C. under argon for 1.25 hours. Crushed ice-water (~1.0) was added slowly and the solution was acidified to PH2 with 6N hydrochloric acid. This was extracted with ether and post-treated in a conventional manner to obtain a brown oily crude product, which was purified using silica gel 600.
Purified by column chromatography on g. Elution with 1:19 to 1:9 ether/petroleum ether (30-60°C) gave 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-4 as a white crystalline powder. -Fluoro-2(E),4(Z)-pentadienoic acid ethyl ester, melting point 50-51°C, was obtained. e 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-4-fluoro-2
Preparation of (E),4(Z)-pentadien-1-ol 86.5 ml (0.13 mol) of diisobutylaluminum hydride (1.5 mol in hexane) are dissolved in 400 ml of anhydrous ether and under argon -
5-(4-methoxy-2,
3,6-trimethylphenyl)-3-methyl-
It was added dropwise to a solution of 14.48 g (0.065 mol) of 4-fluoro-2(E),4(Z)-pentadienoic acid ethyl ester. The resulting mixture was stirred at -65°C under argon for 5 minutes. Further diisobutylaluminum hydride (17 ml, 0.0255 mol) was added again in two portions. The reaction mixture was heated to −65°C.
The mixture was stirred for about 20 minutes and excess hydride was destroyed by adding 85 ml of 1:1 methanol/water dropwise at such a rate that the internal temperature did not exceed -30°C. Then add 100ml of water and mix
Stirred at 10°C for about 40 minutes. The formed precipitate was filtered and thoroughly washed with ether. The resulting layers were separated and the aqueous phase was further extracted with ether. The ethereal phases were combined, washed with water and brine and dried over anhydrous sodium sulfate. Evaporation of the ether to dryness under reduced pressure gave a crude product, which was dissolved in 215 ml of ether, diluted with 60 ml of petroleum ether (30-60 °C) and -
It was kept at 10℃ for 20 hours. The crystals formed were collected, washed with 50 ml of petroleum ether and dried to give pure 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-4-fluoro-
2(E),4(Z)-pentadien-1-ol was obtained as pale yellow crystals, melting point 71-73.5°C. f 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-4-fluoro-2
Preparation of (E),4(Z)-pentadienal 5-(4-methoxy-
13.84 g (0.0524 mol) of 2,3,6-trimethylphenyl)-3-methyl-4-fluoro-2(E),4(Z)-pentadien-1-ol,
Manganese dioxide (54.66
g, 0.629 mol) into the stirred mixture. The resulting mixture was stirred in the dark under argon for 65 hours and worked up as usual to give a yellow crystalline product which was recrystallized from ~1:4 methylene chloride/petroleum ether to give 5. -(4-Methoxy-2,3,6-trimethylphenyl)-3-methyl-4-fluoro-2(E),4(Z)-pentadienal was obtained as yellow crystals, melting point 85-88.5°C. It was done. When the sample was recrystallized once more for analysis, the melting point was 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 of 4-(diethoxyphosphinyl)-2(Z,E)-3-(trifluoromethyl)-crotonic acid ethyl ester in 50 ml of dimethoxyethane
(29.7 mmol) was added dropwise at 0° C. to a suspension of 1.42 g (29.7 mmol) of a 50% dispersion of sodium hydride in oil in 25 ml of dimethoxyethane (the oil was removed by washing with pentane). The resulting mixture was stirred at 23° C. until no more hydrogen gas was evolved (approximately 1 hour). To the resulting brown mixture,
5-(4-methoxy- in 50 ml of dimethoxyethane)
6.59 g of 2,3,6-trimethylphenyl)-3-methyl-2(E),4(E)-pentadien-1-al
(27 mmol) was added dropwise under argon. The resulting reaction mixture was stirred at 23°C under argon for 5.0 h, then poured onto crushed ice-water and adjusted to pH 3 with 2N hydrochloric acid.
and then extracted three times with 250 ml of ether. The ether extracts were combined, washed with water, and dried over anhydrous magnesium sulfate. The ether was evaporated to dryness under reduced pressure to give a brown oil;
This was purified by column chromatography on 300 g of silica gel. 1:19 ether/
Elution with petroleum ether gives a crystalline product, which is further recrystallized from petroleum ether to yield pure 9-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-7- Methyl-2(E),4(E),6(E),8(E)-nonatetraenoic acid ethyl ester was obtained as bright yellow crystals, melting point 72-75°C. 4-(diethoxyphosphinyl)-2(Z,E)-3-(trifluoromethyl)-crotonic acid ethyl ester used in Example 9 could be produced, for example, as follows. Ethyl-3-trifluoromethyl-4-bromo-2(Z,E)-butenoate (18.48 g, 70.7 mmol) and triethyl phosphite (12.95
g, 78 mmol) was heated at 140° C. for 3.0 hours, during which time the ethyl bromide formed during the reaction was distilled off. When the obtained crude product was distilled at 1 mmHg using a Vigreux column, it contained 4-(diethoxyphosphinyl)-2(Z,E)-3-(trifluoromethyl)-crotonic acid ethyl ester. 1:1 mixture of isomers and boiling point of isomers 110
~113℃ Colorless liquid containing mixture, boiling point 105~
A temperature of 110°C was obtained. Example A Wet granulation formulation - 25 mg Tablet Ingredients per tablet Active compound - 2% excess 25.5 mg Modified starch 2.5 mg Pregelatinized starch 2.5 mg Microcrystalline cellulose 3.5 mg Lactose, anhydrous 3.0 mg Magnesium stearate 0.3mg Talc 0.7mg Total weight 38.0mg Procedure 1 Mix all ingredients except magnesium stearate and talc in a suitable mixer. Mill and mix. 2 Granulate with water to a uniform wet consistency. Mill and spread on a plate. 3 Dry overnight in a suitable dryer. 4 mill and premix with magnesium stearate and talc. Mix for 5 minutes. 5 Compress with a suitable press. Example B Direct Compression Formula - 25 mg Tablet Ingredients Quantity per Tablet Active Compound - 2% Excess 25.5 mg Lactose, Anhydrous 172.5 mg Microcrystalline Cellulose (PH101) 25.0 mg Starch 25.0 mg Magnesium Stearate 2.0 mg Total Weight 250 mg Hand Step 1 Mix all ingredients except magnesium stearate in a suitable mixer. 2 Make a premix with magnesium stearate and add to the mixture in step 1.
Mix for 5 minutes. 3 Compress with a suitable press.

Claims (1)

[Claims] 1 formula [wherein R ₁ , R ₂ and R ₃ are lower alkyl, R ₄ is lower alkoxy, R ₆ and R ₈ are methyl or trifluoromethyl, R ₉ is lower alkoxycarbonyl, R ₅ , _R7 ,
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are hydrogen or fluorine, provided that at least one of R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is fluorine, or R ₆
and at least one of R ₈ is trifluoromethyl]. 2 9-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3,7-dimethyl-2(Z),4(E),6(E),8(E)-nonatetraene The compound according to claim 1, which is an acid ethyl ester. 3 9-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3,7-dimethyl-2(Z),4(E),6(Z),8(E)-nonatetraene The compound according to claim 1, which is an acid ethyl ester. 4 9-(4-methoxy-2,3,6-trimethylphenyl)-6-fluoro-3,7-dimethyl-2(E),4(E),6(Z),8(E)-nonatetraene The compound according to claim 1, which is an acid methyl ester. 5 9-(4-methoxy-2,3,6-trimethylphenyl)-6-fluoro-3,7-dimethyl-2(Z),4(E),6(Z),8(E)-nonatetraene The compound according to claim 1, which is an acid methyl ester. 6 9-(4-methoxy-2,3,6-trimethylphenyl)-6-fluoro-3,7-dimethyl-2(E),4(E),6(E),8(E)-nonatetraene The compound according to claim 1, which is an acid methyl ester. 7 9-(4-methoxy-2,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2(E),4(E),6(E),8(E)-nonatetraene The compound according to claim 1, which is an acid ethyl ester. 8 9-(4-methoxy-2,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2(E),4(Z),6(E),8(E)-nonatetraene The compound according to claim 1, which is an acid ethyl ester. 9 9-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-7-trifluoromethyl-2(E),4(E),6(E),8(E)-nonatetraene The compound according to claim 1, which is an acid ethyl ester. 10 9-(4-methoxy-2,3,6-trimethylphenyl)-8-fluoro-3,7-dimethyl-2(E),4(E),6(E),8(Z)-nonatetraene The compound according to claim 1, which is an acid methyl ester. 11 9-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-7-
The compound according to claim 1, which is methyl-2(E),4(E),6(E),8(E)-nonatetraenoic acid ethyl ester. 12 General formula [wherein R ₁ , R ₂ and R ₃ are lower alkyl, R ₄ is lower alkoxy, R ₆ and R ₈ are methyl or trifluoromethyl, R ₉ is lower alkoxycarbonyl, R ₅ , _R7 ,
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are hydrogen or fluorine, provided that at least one of R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is fluorine, or R ₆
and at least one of R ₈ is trifluoromethyl] In producing a polyene compound having the general formula The compound with the general formula [However, in the above formulas a and a, A
and B, one of which is oxo and the other is a triarylphosphonium of the formula -P[Y] ₃ Z, where Y is aryl and Z is an anion of an inorganic or organic acid. or dialkoxyphosphinyl represented by the formula [Formula] (wherein X is alkoxy), R ₁ , R ₂ , R ₃ , R ₄ ,
_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R11 , _R12 and _R13
has the same meaning as shown in the above formula] A method for producing a polyene compound having the above formula. 13 Claims in which the reaction is carried out in the presence of an alkali metal alcoholate, such as sodium methylate, or in the presence of an optionally alkyl-substituted alkylene oxide, such as ethylene oxide or 1,2-butylene oxide, using the conditions of the Witteig reaction. The method according to item 12. 14. A process according to claim 13, wherein the reaction is carried out in an inert organic solvent, preferably in a chlorinated hydrocarbon such as methylene chloride or in dimethylformamide. 15 The reaction is carried out using a base in the presence of an inert organic solvent, preferably using sodium hydride in 1,2-dimethoxyethane or an alkali metal alcoholate in an alkanol, and following the conditions of the Horner reaction. 13. The method according to claim 12, which is carried out using the method according to claim 12. 16 General formula [wherein R ₁ , R ₂ and R ₃ are lower alkyl, R ₄ is lower alkoxy, R ₆ and R ₈ are methyl or trifluoromethyl, R ₉ is lower alkoxycarbonyl, R ₅ , _R10 ,
R ₁₁ , R ₁₂ and R ₁₃ are hydrogen or fluorine, provided that at least one of R ₅ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is fluorine, or at least one of R ₆ and R ₈ is One is trifluoromethyl] In producing a polyene compound having the general formula The compound with the general formula [However, in the above formulas b and b, A
and B, one of which is oxo and the other is a triarylphosphonium of the formula -P[Y] ₃ Z, where Y is aryl and Z is an anion of an inorganic or organic acid. or dialkoxyphosphinyl represented by the formula [Formula] (wherein X is alkoxy), R ₁ , R ₂ , R ₃ , R ₄ ,
R ₅ , R ₆ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ have the same meanings as shown in the above formula ′] A method for producing a polyene compound having the above formula ′, characterized in that . 17 Claims in which the reaction is carried out in the presence of an alkali metal alcoholate, such as sodium methylate, or in the presence of an optionally alkyl-substituted alkylene oxide, such as ethylene oxide or 1,2-butylene oxide, using the conditions of the Witteig reaction. The method according to item 16. 18. A process according to claim 17, wherein the reaction is carried out in an inert organic solvent, preferably in a chlorinated hydrocarbon such as methylene chloride or in dimethylformamide. 19 The reaction is carried out using a base in the presence of an inert organic solvent, preferably using sodium hydride in 1,2-dimethoxyethane or an alkali metal alcoholate in an alkanol, and following the conditions of the Horner reaction. 17. The method according to claim 16. 20 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-
Dien-1-al with 4-(diethoxyphosphinyl)-2-fluoro-3-methylcrotonate ethyl ester or 4-(diethoxyphosphinyl)-2-fluoro-3-methylcrotonate ethyl ester 20. A method according to any one of claims 16 to 19, which comprises reacting. 21 5-(4-methoxy-2,3,6-trimethylphenyl)-2-fluoro-3-methyl-penta-2,4-dien-1-al to 4-(dimethoxyphosphinyl)-3- 20. A method according to any one of claims 16 to 19, which comprises reacting with methyl crotonic acid methyl ester. 22 5-(4-methoxy-2,3,6-trimethylphenyl)-3-trifluoromethyl-penta-2,4-dien-1-al to 4-(dimethoxyphosphinyl)-3-methylcroton 20. A method according to any of claims 16 to 19, comprising reacting with an acid methyl ester. 23 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-4-fluoro-
A process according to any of claims 16 to 19, comprising reacting 2,4-pentadien-1-al with 4-(dimethoxyphosphinyl)-3-methyl-crotonic acid methyl ester. . 24 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadien-1-al to 4-(diethoxyphosphinyl)-3-(trifluoromethyl) - The method according to any of claims 16 to 19, comprising reacting with crotonic acid ethyl ester. 25 General formula [wherein R ₁ , R ₂ and R ₃ are lower alkyl, R ₄ is lower alkoxy, R ₆ and R ₈ are methyl or trifluoromethyl, R ₉ is lower alkoxycarbonyl, R ₅ , _R7 ,
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are hydrogen or fluorine, provided that at least one of R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is fluorine, or R ₆
and at least one of R ₈ is trifluoromethyl] In producing a polyene compound having the general formula The compound with the general formula [However, in the above formulas c and c, A
and B, one of which is oxo and the other is a triarylphosphonium of the formula -P[Y] ₃ Z, where Y is aryl and Z is an anion of an inorganic or organic acid. or dialkoxyphosphinyl represented by the formula [Formula] (wherein X is alkoxy), R ₁ , R ₂ , R ₃ , R ₄ ,
_R5 , _R6 , _R7 , _R8 , _R9 , _R10 , _R11 , _R12 and _R13
has the same meaning as shown in the above formula] A method for producing a polyene compound having the above formula. 26 Claim No. 2, wherein the reaction is carried out in the presence of an alkali metal alcoholate, such as sodium methylate, or in the presence of an alkyl-substituted alkylene oxide, such as ethylene oxide or 1,2-butylene oxide, using the conditions of the Witteig reaction. The method according to item 25. 27. A process according to claim 26, wherein the reaction is carried out in an inert organic solvent, preferably in a chlorinated hydrocarbon such as methylene chloride or in dimethylformamide. 28 The reaction is carried out using a base in the presence of an inert organic solvent, preferably using sodium hydride in 1,2-dimethoxyethane or an alkali metal alcoholate in an alkanol, and following the conditions of the Horner reaction. 26. The method according to claim 25. 29 8-(4-methoxy-2,3,6-trimethylphenyl)-3-fluoro-6-methyl-
Claims 25-28 comprising reacting 3,5,7-octatrien-2-one with (diethoxyphosphinyl)-acetic acid ethyl ester
The method described in any of the paragraphs. 30 General formula [wherein R ₁ , R ₂ and R ₃ are lower alkyl, R ₄ is lower alkoxy, R ₆ and R ₈ are methyl or trifluoromethyl, R ₉ is lower alkoxycarbonyl, R ₅ , _R7 ,
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are hydrogen or fluorine, provided that at least one of R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is fluorine, or R ₆
and R ₈ , at least one of which is trifluoromethyl.] An antitumor agent comprising a polyene compound having the following as an active ingredient. 31 The polyene compound is 9-(methoxy-2,
3,6-trimethylphenyl)-6-fluoro-
3,7-dimethyl-2(E), 4(E), 6(Z), 8(E)-
The antitumor agent according to claim 30, which is nonatetraenoic acid methyl ester.