JPS5951531B2 - Method for producing polyene compounds - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing polyene compounds.

The polyene compounds provided by the present invention have the general formula
[In the formula, one of the symbols R and R2 represents a halogen atom or a lower alkyl group, the other symbol represents a halogen atom or a lower alkoxy group, and the symbols R and R,
each represents hydrogen or a halogen atom or a lower alkyl group, provided that one of the symbols R and R is other than a halogen atom, the symbol R4 represents a lower alkoxy group, and the symbol R represents an alkoxycarbonyl group. and salts thereof.

The lower alkyl groups mentioned preferably contain up to 6 carbon atoms and are, for example, methyl, ethyl, propyl, isopropyl or 2-methylpropyl groups.

Lower alkoxy groups likewise preferably contain up to 6 carbon atoms and are, for example, methoxy, ethoxy or isopropoxy groups. Among the halogen atoms, fluorine and chlorine are preferred.

Alkoxycarbonyl groups preferably include alkoxy groups containing up to 6 carbon atoms. These groups can be straight-chain or branched groups, such as methoxy, ethoxy or isopropoxy groups. However, alkoxy groups also include higher alkoxy groups containing 7 to 20 carbon atoms,
In particular, it may be a cetyloxy group. The alkoxy group may be substituted by a functional group, for example a nitrogen-containing group such as an optionally alkyl-substituted amino or morpholino group, or a piperidyl or pyridyl group. An example of a compound of formula 1 is: 9-(6-chloro-4-
Methoxy-2,-3-dimethyl-phenyl)-3,7-
Dimethylnona-2,4,6,8-tetraene-1-otucic acid ethyl ester, 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethylnona-2,4,6 , 8-tetraene-1-eutschic acid ethyl ester 9-(2-chloro-4-methoxy-3
, 5,6-trimethyl-phenyl)-3,7-dimethyl-mena-2,4,6,8-tetraene-1-eutschic acid ethyl ester, 9-(5-chloro-2,4-dimethoxy-6-methyl-phenyl) )-3,7-dimethylnona-2,4,6,8-tetraene-1-otsuccinic acid ethyl ester, 9-(2,6-dichloro-4-methoxyphenyl)-3,7-dimethylnona-2,4 , 6,8-tetraene-1-otucic acid ethyl ester, 9-(2
,5,6-trichloro-4-methoxyphenyl)-3
, 7-dimethylnona-2,4,6,8-tetraene-1-eucic acid ethyl ester, 9-(6-methyl-2,4-dimethoxyphenyl)-3,7-dimethylnona-2,4,6 , 8-dried traene-1-oitucic acid ethyl ester and 9-(2,4-dimethoxy-3,
6-dimethyl-phenyl)-3,7-dimethylnon-2,4,6,8-tetraene-1-oectic acid ethyl ester.

According to the method provided by the present invention, the compounds of formula I and their salts can be prepared from compounds of the general formula [wherein the symbol m represents o and n represents 1].
or the symbol m represents 1 and n represents o, one of the symbols A and B represents a foilmyl group and the other symbol represents the formula 1 CH, - PCX]. 6YΘ (where the symbol X represents an aryl group and the symbol Y represents an anion of an organic or inorganic acid) represents a triarylphosphonium methyl group: the symbols R, . R2, R3, R4, R, and 2 have the abovementioned meanings], optionally hydrolyzing the resulting polyene compound of formula I, and optionally converting the resulting acid into a salt. Manufactured by changing to

The aryl group represented by the symbol X in the triarylphosphonium methyl group of the above formula includes all generally known aryl groups.

However, the aryl group is preferably a mononuclear aryl group such as phenyl or (lower alkyl)- or (lower alkoxy)-substituted phenyl groups such as tolyl, xylyl, tanthyl and p-methoxyphenyl. Among the inorganic acid anions represented by the symbol Y, chlorine, bromine or iodide ions or hydrosulfate ions are preferred. Among the organic acid anions, tosyloxy ion is preferred. Some of the starting materials in the formula are new. Such novel starting materials also form part of the present invention.

These can be manufactured, for example, by the following method. In the case where the symbol m represents 0 and the symbol A represents a triarylphosphonium methyl group [a], the compound of the formula [a] can be obtained by, for example, preparing the corresponding (R, ~R,)-benzene in the presence of a hydrohalic acid ( treatment with formaldehyde (for example, optionally in the presence of concentrated hydrochloric acid in a solvent, especially glacial acetic acid);
The resulting (R, ~R,)-benzyl halide [symbol m is o
and symbol A represents a halomethyl group (i)
halides of the formula] can be prepared in a manner known per se by reaction with triarylphosphines in a solvent, preferably with triphenylphosphine in toluene or benzene.

Alkoxy groups can be introduced into the above-mentioned (R, ~R5)-benzenes, for example, by alkylation of the hydroxy groups already present.

For example, the corresponding phenol can be reacted with an alkyl halide (eg methyl iodide) or dimethyl sulfate, preferably in a solvent (eg an alkanol) and in the presence of a base (eg potassium carbonate). Compounds of the formula in which the symbol m represents 1 and the symbol A represents a triarylsulfonium methyl group [b] can be prepared, for example, in the following manner: first the corresponding (R, ~R$)benzene is Formylation: For example, the (R, ~R,)-benzene is treated with a formylating agent.

This can be done, for example, by carrying out formyl in the presence of Lewis acid. As formylating agents, mention may be made in particular of orthoformic acid esters, formyl chloride and dimethylformamide. Particularly suitable Lewis metals include zinc, aluminum, titanium,
Halides of tin and iron, such as zinc chloride, aluminum trichloride, titanium tetrachloride, tin tetrachloride and iron trichloride, and halides of inorganic and organic acids, such as phosphorous oxychloride and methanesulfonyl chloride. When the formylating agent is present in excess. Formylation can be carried out without further addition of solvent.

However, it is generally preferable to carry out the formylation in an inert organic solvent (eg nitrobenzene or a chlorinated hydrocarbon such as methylene chloride). This formylation can be carried out at a temperature between 0° C. and the boiling point of the formylation mixture. The (R,~R,)-benzaldehyde obtained is then treated in a manner known per se with acetone in the presence of an alkali (e.g. dilute aqueous sodium hydroxide solution) in the cold (i.e. at a temperature of about 0°C to 30°C). Condensation is carried out to give (R, ~R5)-phenylbut-3-en-2-one, which is subjected to an organometallic reaction [e.g. Grignard by addition of acetylene] in a manner known per se.
Grignard) reaction] to the corresponding (R, ~R
5)-phenyl-3-methyl-3-hydroxy-pent-4-en-1-yne.

The resulting tertiary acetylenic carbinol is then treated with a partially inactivated noble metal catalyst in a manner known per se.
Partially hydrogenated using a Lindlar catalyst. The resulting tertiary ethylenic carbinol is then converted into a triarylphosphine, especially a triphenyl carbinol, in the presence of an inorganic acid (eg a hydrogen halide such as hydrogen chloride or hydrogen bromide or sulfuric acid) in a solvent (eg benzene). Treatment with phosphine gives the symbol m under allylic rearrangement.
represents 1 to the desired phosphonium salt of formula b. A compound of the formula [c] where the symbol m represents 0 and the symbol A represents a formyl group can be produced, for example, by formylating (R, to R,)-benzene by the method described above.

When the symbol m represents 1 and the symbol A represents a formyl group [d], the compound of the formula is, for example, Pitzteich (Wit
tig) Under reaction conditions (R,~R5)-phenyl-but-3-en-2-one (as described above in connection with the preparation of compounds of formula b) is converted into ethoxycarbonyl-methylene-triphenylphosphorane or diethyl - It can be produced by reacting with phosphonic acid ethyl ester.

The resulting (R, ~R,)-phenyl-3-methyl-
Penta-2,4-diene-1-otsuccinic acid ethyl ester is cold reduced with a complex metal hydride, especially lithium aluminum hydride, in an organic solvent (e.g. ether or tetrahydrofuran) to form (R, ~R, )-phenyl-3-methyl-penta-2,4-dien-1-ol. This alcohol is then oxidized by treatment with an oxidizing agent (e.g. magnesium dioxide in an organic solvent such as acetone or methylene chloride) at a temperature between 0°C and the boiling point of the oxidation mixture to give the desired (R, ~R ,)-phenyl-3-methyl-penta-2,4-diene-1-al. Some of the compounds of formula are new.

When the symbol n represents 0 and the symbol B does not represent a triarylphosphonium methyl group [a], the compound of the formula is:
The esterifiable 4-3-methyl-crotyl alcohol or the esterified 4-halo-3-methyl-crotyl alcohol is reacted with triarylphosphine in a solvent, preferably triphenylphosphine in toluene. can be easily manufactured.

When the symbol n represents 1 and the symbol B represents a triarylphosphonium methyl group [b], the compound of the formula is:
For example, when the symbol n represents 1 and the symbol B represents a formyl group [d], the formyl group in the aldehyde of formula [d] can be replaced with a metal hydride such as sodium borohydride in an alkanol (e.g. ethanol or isopropanol). Reduces to hydroxymethyl group.

The resulting alcohol is halogenated using common halogenating agents (e.g. phosphorus oxychloride) to form a halide of the formula 8-halo-1, where the symbol n represents 1 and the symbol B represents a halomethyl group [i]. 3,7-dimethyl-octa-2,4,6-triene-1-carboxylic acid or a derivative thereof is reacted with the desired formula b with triarylphosphine in a solvent, preferably triphenylphosphine in toluene or benzene. Can be converted to phosphonium salts.
Compounds of the formula [C] in which the symbol n represents 0 and the symbol b represents a formyl group can be prepared, for example, by oxidative cleavage of optionally esterified tartaric acid (e.g. in an organic solvent such as benzene). (using lead tetraacetate) at room temperature.

The glyoxalic acid derivative obtained is then condensed with propionaldehyde in a manner known per se, preferably in the presence of an amine, at elevated temperatures (for example temperatures between 60° C. and 110° C.) with removal of water. and the desired 3-
Formyl crotyl alcohol derivatives can be produced. When the symbol n represents 1 and the symbol B represents a formyl group [d], the compound of the formula is, for example, 4,4-dimethoxy-3-methylbut-1-ene-3- in the presence of a tertiary amine. The ol is reacted with phosgene when cold, preferably at -10°C to -20°C, and the resulting 2-formyl-4-chlorobut-12-ene is converted into 3-formylcrotonic acid or 3-formylcrotonic acid, which can be esterified, under Bitteig reaction conditions. It can be condensed with 3-formylcrotyl alcohol which can be esterified to produce the desired albihyde of formula d. According to the method provided by the present invention, a phosphoniwam salt of formula a or b is converted to a phosphoniwam salt of formula d
or reacting with an aldehyde of formula c or reacting a phosphonium salt of formula a or b with an aldehyde of formula d or c.

According to the Bitteig method, the components are bonded together in the presence of an acid binder (for example an alkali metal alcoholate such as sodium methylate or an optionally alkyl-substituted alkylene oxide, in particular ethylene oxide or 1,2-butylene oxide). The reaction is carried out at a temperature between room temperature and the boiling point of the reaction mixture, or optionally in a solvent (for example, a chlorinated hydrocarbon such as methylene chloride, or dimethylformamide).

According to the Horner method, each component is combined with a base, preferably in the presence of an inert organic solvent, such as sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran or 1,2-dimethoxyethane, or methanol. The reaction is carried out at a temperature between 0° C. and the boiling point of the reaction mixture.

According to the Julia method. The components are reacted with one another using a condensing agent, preferably in the presence of a polar solvent. Suitable solvents include, for example, dimethylformamide,
Dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran and hexamethylphosphoric triamide and alcohols such as methanol, isopropanol or tert-butanol. Among the strong bases which are particularly utilized as binders, for example alkali metal and alkaline earth metal carbonates, especially sodium carbonate, alkali metal hydroxides such as potassium hydroxide or sodium hydroxide, alkali metal and alkaline earth metal alcoholates such as Mention may be made of sodium methylate and especially potassium tert-butyrate, alkali metal hydrides such as sodium hydride, alkyl-magnesium halides such as methylmagnesium bromide, and alkali metal amides such as sodium amide. Reactions using this method are preferably carried out at low temperatures, especially at freezing temperatures (e.g. -50° to -8
(0°C) or below. It has been found that in some cases it is advantageous to carry out the above reactions in situ:
That is, without isolating the particular phosphonium salt from the medium in which it was produced. The carboxylic esters of the formula I can be hydrolyzed to the carboxylic acids in a manner known per se, for example by treatment with an alkali, in particular water-alcoholic sodium hydroxide or potassium hydroxide, at room temperature to the boiling point of the mixture. I can do it.

Compounds of formula I can occur as cis/trans mixtures, which can be separated into cis and trans components in methods known per se or can be isomerized to all-trans compounds in methods known per se. I can do it.

The present polyene compounds are pharmacologically valuable.

The compound is effective against benign and malignant neoplasia (NeOplasia).
) and premalignant lesions, and for the systemic and local prevention of these conditions. The compound also treats acne, psoriasis, and increased or pathologically altered keratosis.
Other skin diseases (DermatoOs) associated with
e) Local and systemic treatment of inflammatory diseases and allergic dermatological symptoms (Allergic dermatol)
It is also suitable for the treatment of OnditiOn). This compound may also cause inflammation or degeneration or metaplastic changes (MetaplasticalteratiOn).
mucosal diseases caused by
It can be used for the control of P. elegans. The toxicity of this polyene compound is minimal.

For example, 9-(2-chloro-4-methoxy-3,5
, 6-trimethyl-phenyl)-3,7-dimethylnon-2,4,6,8-tetraene-1-otucic acid to mice weighing 30 y at 200 doses per day. When administered intramembraneally at a dosage of NgA, after 14 days [administration for a total of 10 days], A-Hypervitaminosis (A-Hypervitaminosis)
No signs of nOsis) were evident. The first signs of slight A-vitaminosis in mice appear after 14 days at a dosage of 4007 V/Kg per day [total administration for 10 days]. This results in a 20% weight gain, some hair loss and slight flaking of the skin. The tumor (TumOur) suppressive activity of this polyene compound is remarkable.

In the Papilloma test, tumors induced by dimethylbenzoanthracene and lotus oil regress. The diameter of the papilloma is 9-(2-chloro-4-methoxy-3,5,6-trimethyl-phenyl)-3,7
-dimethylnona-2,4,6,8-tetraene-1-
Within 2 weeks after intraperitoneal administration of otsucic acid ethyl ester, 61% and 2007 at a dose of 400 mf/Kg/week.
45 (F6) at a dosage of 7 V/Kg/week. The polyene compounds of formula 1 and their salts can therefore be used as pharmaceuticals, e.g. in pharmaceutical preparations containing the compounds in combination with compatible pharmaceutical carriers. Pharmaceutical preparations for systemic administration can be prepared, for example, by incorporating the polyene compound as the active ingredient in the non-toxic, inert solid or liquid carriers that are conventional for such preparations.

Pharmaceutical preparations can be administered enterally or parenterally.

Preparations suitable for enteral administration are, for example, tablets, capsules, dragees, syrups, suspensions, solutions and suppositories; preparations suitable for parenteral administration are cold infusions and solutions for injection. The dosage at which the polyene compounds of the invention are administered can vary according to the method and route of administration and the needs of the patient.

The polyene compounds of the present invention can be administered from 51!1f to 2001! at one or more dosages per day. l! can be administered in an amount of

Capsules containing from about 107!f to about 100 w of the polyene compound of this invention are the preferred form of administration. Pharmaceutical preparations may contain inert or pharmacologically active additives.

Tablets or granules can contain, for example, a series of binders, fillers, carrier substances or diluents. Liquid preparations can take the form of sterile, water-miscible solutions, for example. Capsules are fillers or thicls.
ener).

Additionally, flavor-improving additives and preservatives are included in drug preparations.
Stabilizers, water retention agents or emulsifiers, salts for changing the osmotic pressure, substances commonly used as buffers and other additives may be present. The carrier substances and diluents mentioned above may be organic or inorganic substances, such as water, gelatin, lactose,
It can include starch, magnesium stearate, talc, gum arabic, polyalkylene glycols, and the like.

Of course, it is a prerequisite that all adjuvants used in the manufacture of this pharmaceutical preparation are non-toxic. For topical administration, the polyene compounds may be formulated into ointments, tinctures, creams, solutions,
Advantageously, they are in the form of lotions, sprays, suspensions and the like.

Ointments, creams and solutions are preferred. The pharmaceutical preparations for topical administration can be prepared by mixing the polyene compound as the active ingredient with non-toxic, inert solid or liquid carriers which are customary for such preparations and suitable for topical treatment. Advantageous for topical administration are from about 0.10 to about 0
．． 3%, preferably 0.0296 to 0.1% solution and about 0.05% to about 5%, preferably about 0.1 (Fll to about 2.0% ointment or cream).

Antioxidants (eg tocopherols, N-methyl-gamma-tocopheramine, butylated hydroxyanisole or butylated hydrothousitoluene) may also be present in the drug preparation.

The following examples illustrate the methods provided by the present invention. For the formula (1) produced in the following examples
The yields of the target compounds are all within the range of 60 to 90%.

Example 1 9.9 fi of 2-chloro-4-methoxy-3,5,6-trimethyl-pendyltriphenylphosphonium chloride was dissolved in 50 m2 of dimethylformamide.

After addition of 416f of 7-formyl-3-methyl-octa-2,4,6-triene-1-eutschic acid ethyl ester, the solution was dissolved at 20°C in freshly prepared sodium chloride from 0.460 r of sodium and 10 g of absolute ethanol. Treated dropwise with ethylate solution.

The mixture was stirred at room temperature for 12 hours, then 100 m2 of water
and extracted with hexane. The hexane extract was shaken three times with methanol/water, dried over sodium sulphate and evaporated under reduced pressure. The residue was adsorbed onto silica gel and eluted with methylene chloride/hexane (8:2).
It was purified using 9-(2
-chloro-4-methoxy-3,5,6-trimethyl-phenyl)-3,7-dimethyl-octa-2,4,6,8
-Tetraene-1-oitsucic acid ethyl ester was recrystallized from hexane and then melted at 90°C. 2-chloro-4-methoxy-3,5,6-trimethylbenne used as a starting material. Dilutetribenylphosphonium chloride could be prepared, for example, as follows: 3
-chloro-4,6-dimethyl-benzyl chloride 18
9V was introduced into 1500mE of 5N sodium hydroxide.

While stirring this mixture, add 195 y of zinc powder within 2 hours.
Processed with. The exothermic reaction temperature can be reduced by cooling7.
It was kept at 0°C. The mixture was further stirred at 50° C. for 12 hours and then filtered. The furnace liquor was extracted three times with 800 ml of methylene chloride. The methylene chloride extract was washed neutral with water, dried over sodium sulphate and evaporated.
The remaining 2-chloro-3,5,6-trimethyl-benzene was adsorbed onto silica gel and eluted with hexane/
Purification was performed using methylene chloride (9:1). This compound boiled at 81°C/9% Hg. 2-chlor-3,
While stirring 5,6-trimethyl-benzene 70V
It was added dropwise within 30 minutes to 400 μm of nitric acid (70% V/V) pre-cooled to ℃.

The mixture was stirred for a further 4 hours while gradually increasing the temperature to +20° C., then introduced into ice water and thoroughly extracted with ether. The ether extract was washed 6 times with 1000 mg, dried over sodium sulfate and evaporated under reduced pressure. The remaining 2-chloro-4-nitro-3,5,6-trimethylbenzene was adsorbed onto silica gel and purified using hexane/benzene (3:7) for elution. This compound melted at 79° C. after recrystallization from low boiling petroleum ether. 114.5 V of 2-chloro-4-nitro-3,5,6-trimethyl-benzene was dissolved in 300 ml of ethyl acetate.

The solution was diluted with 300 ml of ethanol and, after addition of 20 ml of Raney nickel, hydrogenated under normal conditions.
After absorption of hydrogen 4377Z1, hydrogenation was completed. The catalyst was separated from the furnace while bubbling with carbon dioxide and washed with ethanol. The combined furnace liquors were evaporated under reduced pressure. The remaining 4-amino-2-chloro-3,5,6-trimethyl-benzene was recrystallized from hexane. It melted at 93°C. 4-
65 V of amino-2-chloro-3,5,6-trimethyl-benzene were slowly introduced into 250 ml of concentrated sulfuric acid with stirring and cooling.

During this time the temperature rose to +60°C. Add this mixture to 7 ice cubes.
Gradually add 50'Ii and cool to oC, then add 80'Ii of water
It was treated dropwise within 3 hours with a solution of 26.4y of sodium sulfite in m1. The mixture was stirred for a further 90 minutes at o<0>C to +10<0>C and then filtered. The filtrate was diluted with sulfuric acid [50
Steam distillation was carried out while dropping 600 ml of [V01%]. The resulting product was extracted three times with 100 ml of methylene chloride.

The methylene chloride extract was dried over sodium sulphate and evaporated. The remaining 2-chloro-4-hydroxy-
3,5,6-trimethyl-benzene was recrystallized from hexane and then melted at 97°C. After addition of 400 ml of methanol and 85.5 ml of dimethyl sulfate, 2-chloro-
Potassium hydroxide [25911, g
/V] 265.5 ml.

The mixture was then heated to boiling, stirred for a further 4 hours under reflux conditions and then evaporated. Pour the residue into 600ml of water
I was hired by The aqueous solution was extracted three times with ether 6007n1. The ether extract was washed neutral with water, dried over sodium sulphate and evaporated under reduced pressure. The remaining oily 2-chloro-4-methoxy-3,5,6-trimethyl-benzene boiled at 77-79°C/1 nHV.
2-chloro-4-methoxy-3,5,6-trimethyl-
Benzene 65.35V was converted into acetic acid 23577Ze, hydrochloric acid [3
7V/V] 446ml and formaldehyde (35%)
1074 was mixed.

This mixture was stirred at 70°C for 3 hours, and after cooling, 200°C of water was added.
I guided it to 0m1. This aqueous solution was mixed with 1000 methylene chloride.
Extracted 3 times with Aoi. Add methylene chloride extract to 1000ml of water.
Washed 3 times with 1 ml, dried over sodium sulfate and evaporated.

The remaining 2-chloro-4-methoxy-3,5,6-trimethyl-benzyl chloride was adsorbed onto silica gel and purified using low boiling petroleum ether for elution.
This compound melted at 59°C to 63°C after recrystallization from low boiling petroleum ether. 2-chloro-4-methoxy-3,
70.8 r of 5,6-trimethyl-benzyl chloride was dissolved in 500 mt of toluene.

This solution was treated with triphenylphosphine J Mo Vr and
The mixture was stirred at 00°C for 18 hours. 2- isolated as white crystals
The chloro-4-methoxy-3,5,6-trimethyl-pendyltriphenylphosphonium chloride was washed with ether and dried under vacuum. This phosphonium salt is 2
It melted at 15°C. The 7-formyl-3-methyl-octa-2,4,6-triene-1-otucic acid ethyl ester used as starting material could be prepared, for example, as follows: addition of a small amount of iron nitrate (). After that, 2700 mt of liquid ammonia. was treated with potassium 169.5 V in portions with stirring and cooling.

As soon as the initial blue color disappears (i.e. after about 30-45 minutes)
, add 3 tons of acetylene gas until the dark color of the mixture becomes lighter.
It was introduced with a minute airflow. The gas flow was then reduced to 2 t/min and the mixture was mixed with 425 mI of anhydrous ether! A solution of 500 tons of methylglyoxal dimethyl acetal was added dropwise to the solution. Acetylene bubbling was continued with stirring for an additional hour.
This mixture was then treated in portions with ammonium chloride 425y, evaporating the ammonia for 30 minutes in 12 hours.
The mixture was gradually warmed to 0.degree. C. and extracted with 1600 m.sup.2 of ether.
The ether extracts were dried over sodium sulphate and evaporated under reduced pressure. The remaining 4,4-dimethoxy-3-methyl-but-1-yn-3-ol was purified at 33°C/0.0 after rectification.
Boiled with 3 sin Hg: NS = 1.4480. 4,4-dimethoxy-3-methyl-but-1-yn-3-ol 1
98f was dissolved in 960mt of high boiling point petroleum ether, and 5
After addition of 19.3 t of % palladium catalyst and 193 t of quinoline, hydrogenation was carried out under normal conditions.

After absorbing 33.5 tons of hydrogen, the hydrogenation was completed. The catalyst was filtered off. The filtrate was evaporated under reduced pressure. The remaining 4,4-
After rectification, dimethoxy-3-methyl-but-1-en-3-ol was boiled at 70-72°C at 181 tItHg. 195 mt of phosgene was converted to 157 mt of carbon tetrachloride at -10°C.
It was introduced at 0m2. After addition of 213r of pyridine, the solution was treated dropwise with 327r of 4,4-dimethoxy-3-methyl-but-1-en-3-ol at a temperature of -10°C to -20°C. The mixture was gradually warmed to 25°C with stirring, stirred for a further 3 hours at room temperature, cooled to 15°C,
Wednesday 8957! V! ．． Processed with. The aqueous phase was separated and discarded. After standing cold for 12 hours, the organic phase was dissolved in 5% sulfuric acid 4
48 mt, stirred for 5 hours, then washed with water, dried over sodium sulphate and evaporated under reduced pressure. The remaining 2-formyl-4-chlorobut-12-ene is purified after rectification.
Boiled at 37L~40℃/1.8mlHg; NS=1
．． 4895.165.7 t of 2-formyl-4-chlorobut-12-ene was dissolved in 840 m2 of benzene and treated with 367 t of triphenylphosphine.

The mixture was heated to boiling under reflux conditions with nitrogen bubbling for 12 hours, then cooled to 20°C. The precipitated 2-formylbut-12-ene-4-triphenylphosphonium chloride was washed with benzene and dried, then the 2-formylbut-12-ene-4-triphenylphosphonium chloride
Melted at 50-252°C. 2-formilubute 2-
En-4-triphenylphosphonium chloride 212
．． 6r and 3-formylcrotonic acid ethyl ester 9
5f was introduced into 100 m2 of butanol and treated at 5°C with a solution of 57 t of triethylamine in 60 ml of butanol.

The mixture was stirred at 25° C. for 6 hours, then cooled, introduced into water and thoroughly extracted with hexane. The hexane phase was first washed repeatedly with methanol/water (6:4), then with water, dried over sodium sulfate and filtered.
The furnace liquor was isomerized by shaking with iodine for 12 hours. Iodine was removed by addition of sodium thiosulfate. The filtrate was washed again with water, dried and evaporated under reduced pressure. The remaining 7-formyl-3-methyl-octa-2,4,6-triene-1-oectic acid ethyl ester could be used in the present process without further purification. Example 2 39t of 2,6-dichloro-4-methoxypendyltriphenylphosphonium chloride and 16t of 7-formyl-3-methyl-octa-2,4,6-triene-1-oituic acid ethyl ester were converted into 1,2- Butylene oxide 40V
After the addition, the mixture was heated to 824-85° C. for 2 hours under reflux conditions with stirring.

This mixture was then thoroughly extracted with hexane. The hexane extract was washed several times with methanol/water (60:40), dried over sodium sulphate and evaporated under reduced pressure. The residue was purified using silica gel adsorption and hexane for elution. 9-(2,6,
-dichloro-4-methoxyphenyl)-3,7-
Dimethyl-octa-2,4,6,8-tetraene-1
- After recrystallizing otsucic acid ethyl ester from hexane,
It melted at 117°-118°C. The 2,6-dichloro-4-methoxy-benzyl-triphenylphosphonium chloride used as starting material could be prepared, for example, as follows: 3,5-dichloro-anisole J model.
VV was dissolved in 250 liters of ether.

After adding formaldehyde [35%, V/V] rumored to be 70%,
Hydrogen chloride was bubbled through the solution for 8 hours with stirring at room temperature. The solution was then poured onto water and thoroughly extracted with ether. The ether extract was washed neutral with water, dried over sodium sulphate and evaporated under reduced pressure. remaining oily 2
, 6-dichloro-4-methoxy-benzyl chloride had a refractive index n=15730. 2,6-dichloro-4-methoxy-benzyl chloride 23.7V,
Triphenylphosphine 26.2f and anhydrous benzene 1
50 minutes was heated under reflux conditions for 12 hours.

The 2,6-dichloro-4-methoxy-benzyl-triphenylphosphonium chloride that precipitated on cooling was dried under vacuum before use in the process. Example 3 In a manner similar to that described in Examples 1 and 2, 2-chloro-4-methoxy-5,6-dimethyl benzyl-triphenylphosphonium chloride was converted to 7-formyl-3
-Methyl-octa-2,4,6-triene-1-otucic acid ethyl ester to give 9-
(2-chloro-4-methoxy-5,6-dimethyl-phenyl)-3,7-dimethylnona-2,4,6,8
-tetraene-1-oetsucic acid ethyl ester was obtained.

2-chloro-4-methoxy- used as starting material
5,6-dimethyl-pendyltriphenylphosphonium chloride is prepared in a manner similar to that described in Examples 1 and 2, starting from e.g. 2,3-dimethyl-aniline,
3-dimethyl-5-nitro-aniline, 2,3-dimethyl-5-nitrophenol, 2,3-dimethyl-5-nitroanisole, 2,3-dimethyl-5
-Aminoanisole, 2,3-dimethyl- 5 -
Chloro-anisole and 2-chloro-4-methoxy-5
, 6-dimethyl-benzyl chloride. Example 4 In the same manner as described in Examples 1 and 2, 2, 3, 6
-trichlor-4-methoxy-benzyl-triphenylphosphonium chloride to 7-formyl-3-
Reacted with methyl-octa-2,4,6-triene-1-oectic acid ethyl ester, melting point 126° to 128°C.
9-(2,3,6-trichloro-4-methoxyphenyl)-3,7-dimethylnona-2,4,6,8
-tetraene-1-oetsucic acid ethyl ester was obtained.

2,3,6-trichlor-4 used as starting material
-Methoxy-benzyl-triphenylphosphonium chloride was prepared in the same way as described in Examples 1 and 2.
Starting from 3,5-trichlorophenol. 2, 3,
It could be produced via 5-trichloroanisole and 2,3,6-trichloro-4-methoxypenzyl chloride. Example 5 In a manner similar to that described in Examples 1 and 2, 2,4-dimethoxy-3,6-dimethyl-benzyl-triphenylphosphonium chloride was converted to 7-formyl-3-methyl-octa-2,4,6 9-(2,-4-dimethoxy-3,6-dimethyl-phenyl)-3,7-dimethylnona-2,4,6,8-tetraene-1- Outsucic acid ethyl ester was obtained.

9-(2,4-dimethoxy-3,6-dimethyl-phenyl) obtained by saponifying the above ester] -3,7
-dimethylnona-2,4,6,8-tetraene-1-
Oucic acid melted at 214°-215°C.

2,4-dimethoxy-3,6- used as starting material
Dimethyl-benzyltriphenylphosphonium chloride is prepared in a manner analogous to the method described in Examples 1 and 2, for example starting from orcine (3,5-dihydroxy-toluene), 2-acetyl-3,5-dihydroxy-toluene, 2-acetyl-3,5-dihydroxy-p-xylol, 2,6-dihydroxy-p-xylol, 2,6
-dimethoxy-p-xylol and 2,2. It could be produced via 4-dimethoxy-3,6-dimethyl-benzyl chloride.

Example 6 In a manner similar to that described in Examples 1 and 2, 6-chloro-4-methoxy-2,5-dimethyl-benzyl-triphenylphosphonium chloride was converted to 7-formyl-3-methyl-octa-2,4, By reacting with 6-triene-1-oucic acid ethyl ester, the melting point is 106-107°C.
9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethylnona-2,4,6,
8-tetraene-1-eucic acid ethyl ester was obtained.

6-chloro-4-methoxy-2, used as starting material
5-Dimethyl-pendyltriphenylphosphonium chloride can be prepared analogously to the methods described in Examples 1 and 2, for example, starting from 3-chloro-2,5-dimethyl-nitrobenzene, 3-chloro-2,5- Dimethyl-aniline, 3-chloro-2,5-dimethyl-phenol, 3-
Chlor-2,5-dimethyl-anisole and 6-chloro-4-methoxy-2,. It could be produced via 5-dimethyl-benzyl chloride.

Example 7 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethylnona-2,4,6,8
-Tetraene-1-otucic acid ethyl ester 41r was dissolved in 750 m2 of ethanol.

This solution was treated with 41 t of potassium hydroxide in 63 m2 of water, heated to boiling under nitrogen atmosphere for 30 minutes, cooled,
It was diluted with water and made acidic with hydrochloric acid. Precipitated 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-
3,7-dimethylnona-2,4,6,8-tetraene-1-eucic acid melted at 231-234°C. Example 89-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethylnona-2,4
, 15 t of 6,8-tetraene-1-eucic acid was dissolved in 750 ml of tetrahydrofuran.

The obtained solution was dissolved in phosphorus trichloride 2.46 m2 (0.7 m01
), and after 12 hours, it was concentrated to half its volume under reduced pressure at 30°C and added dropwise to a tetrahydrofuran solution containing 14.6f of ethylamine at 0~5°C. The mixture was stirred at room temperature for 1 hour, introduced into saturated aqueous sodium chloride solution and extracted with methylene chloride. The extract was washed with aqueous sodium chloride, dried and evaporated under reduced pressure. The remaining 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethylnona-2,4,6,
8-Tetraene-1-oectic acid ethylamide was purified by adsorption onto silica gel and using methylene chloride/methanol (90:10) for elution. After recrystallization from ethyl acetate, this ethylamide is 202E-203
Melted at °C. Example 9 36.5f of 1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-triene-j[triphenylphosphonium bromide] was added to 200m of dimethylformamide.
It was dissolved in 2.

4-Methoxy-2,6-dichloropenzaldehyde 14
After adding r, the solution was cooled to 10° C. and a solution of 1.64 r of sodium in 40 ml of ethanol was added dropwise.

The reaction mixture was stirred at room temperature for 12 hours and then poured into 500 mt of methanol/water (60:40). The methanolic solution was thoroughly extracted with hexane and the hexane extract was washed with methanol/water (60:40) and water, dried over sodium sulfate and evaporated. 9 to remain
-(4-methoxy-2,6-dichlorophenyl)-3,
7-dimethylnona-2,4,6,8-tetraene-1
-Ethyl ethyl ester has a melting point of 117°C to 118°C.
(from hexane). Example 10 5-(2-chloro-4-methoxy-3,5,6-trimethylphenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphonium bromide was dissolved in dimethylformamide under nitrogen atmosphere. Added to 910me.

Suspension of sodium hydride 17.5f7 (50% in mineral oil)
) was then added at 5-10° C. within 20 minutes. The reaction mixture was stirred at 10°C for 1 hour, after which 61.8r of 3-formylcrotonic acid ethyl ester was added dropwise at 5-8°C. The reaction mixture was heated to 65° C. for 2 hours, poured into 8 t of ice water, and after adding 300 y of sodium chloride, it was thoroughly extracted with 18 t of hexane. The extracts were washed with methanol/water (6:4) and water, dried and evaporated under reduced pressure. The remaining 9-(2-chloro-4-methoxy-3
, 5,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraene-1-oectic acid ethyl ester has a melting point of 88°C to 89°C. Example
11 In a manner similar to that described in Examples 1 and 2, 2,4-
By reacting dimethoxy-3-chloro-5,6-dimethyl-benzyl-triphenylphosphonium chloride with 7-formyl-3-methyl-octa-2,4,6-triene-1-oitucic acid ethyl ester, a melting point of 95 9-(2,4-dimethoxy-3-chloro-5,6-dimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraene-1-oituic acid ethyl ester at ~96°C Obtained.

The 2,4-dimethoxy-3-chloro-5,6-dimethyl-benzyl-triphenylphosphonium chloride used as starting material can be prepared, for example, from 2-chloro-4,5-dimethyl-resorcin by a method known per se. It can be prepared via chloro-1,3-dimethoxy-4,5-dimethyl-penzole and 3-chloro-2,4-dimethoxy-5,6-dimethylbenzyl chloride.

Example 12 In the same manner as described in Examples 1 and 2. 2,3-
Dimethyl-4-methoxy-6-bromo-benzyl-triphenylphosphonium chloride was converted into 7-formyl-3-
By reacting with methyl-octa-2,4,6-triene-1-oectic acid ethyl ester, a melting point of 114
9-(2,3-dimethyl-4-methoxy-6-promophenyl)-3,7-dimethylnon-2,4,6,8-tetraene-1-eutschic acid ethyl ester having a temperature of 115 DEG C. was obtained.

The 2,3-dimethyl-4-methoxy-6-promopendyltriphenylphosphonium chloride used as a starting material is prepared by a known method, for example, 2,3
-dimethyl-5-nitro-aniline to 2,3-dimethyl-5-nitrophenol, 2,3-dimethyl-5-nitroanisole, 2,3-dimethyl-5-aminoanilin, 2,3- It can be produced via dimethyl-5-promoanisole and 2,3-dimethyl-4-methoxy-6-promoopendylchloride.

Example 13 In a manner similar to that described in Examples 1 and 2, 2-fluoro-4-methoxy-5,6-dimethyl-benzyl-triphenylphosphonium chloride was prepared from 7-formyl-3
- Methyl to octa-2,4,6-triene-1-oitucic acid ethyl ester, melting point 10
9-(2-fluoro-5,6-dimethyl-4-methoxyphenyl)-3,7-dimethylnona-2,4,6,8-tetraene-1-oituic acid ethyl ester at a temperature of 6 to 107°C was obtained. It was done.

2-Fluoro-4-methoxy-5 used as starting material
,6-dimethyl-benzyl-triphenylphosphonium chloride can be prepared by a method known per se, for example, 5-dimethyl-benzyl-triphenylphosphonium chloride.
It can be produced from fluoro-2,3-dimethyl-anisole via 2-fluoro-4-methoxy-5,6-dimethyl-benzyl chloride.

The following reference examples illustrate representative drug preparations provided by the present invention.

Reference Example A The capsule agent may contain the following ingredients: Reference Example B
An ointment containing 2.0% of active ingredient could be prepared using the following ingredients: 9-(2-chloro-4-methoxy-3,5,6-trimethyl-phenyl)-3,7- dimethyl nona-2,4,
6,8-tetraene-1-otucic acid ethyl ester 2
．． 0y Cetyl Alcohol 2.77 Lanolin 6.0t Yellow Querin 15.0t Distilled water, sufficient amount to make 100f.

Claims (1)

[Claims] 1. The compound of general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) The compound of general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) [In each formula,
One of the symbols R_1 and R_2 represents a halogen atom or a lower alkyl group, and the other symbol represents a halogen atom or a lower alkoxy group; the symbols R_3 and R_5 represent hydrogen, a halogen atom, or a lower alkyl group, respectively; however, the symbols R_3 and One of R_5 shall be other than a halogen atom; the symbol R_4 represents a lower alkoxy group; the symbol R_6 represents an alkoxycarbonyl group; the symbol m represents 0 and n represents 1, or the symbol m represents a 1 and n represents 0; one of the symbols A and B represents a formyl group and the other symbol represents the formula -CH_2-P[X]_3^■Y^■ (wherein
The symbol Y represents an aryl group and the symbol Y represents an anion of an organic or inorganic acid. There is▼(
I) [In the formula, symbols R_1, R_2, R_3, R_4,
R_5 and R_6 have the above meanings]. A method for producing a polyethylene compound. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The compound of (II) is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) [In each formula,
One of the symbols R_1 and R_2 represents a halogen atom or a lower alkyl group, and the other symbol represents a halogen atom or a lower alkoxy group; the symbols R_3 and R_5 represent hydrogen, a halogen atom, or a lower alkyl group, respectively; however, the symbols R_3 and One of R_5 shall be other than a halogen atom; the symbol R_4 represents a lower alkoxy group; the symbol R_6 represents an alkoxycarbonyl group; the symbol m represents 0 and n represents 1, or the symbol m represents a 1 and n represents 0; one of the symbols A and B represents a foilmyl group and the other symbol represents a formula -CH_2-P[X]_3^■Y^■ (where the symbol X represents an aryl group); and the symbol Y represents an anion of an organic or inorganic acid) is reacted with a compound of the triarylphosphonium methyl group] to obtain the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I)
[In the formula, symbols R_1, R_2, R_3, R_4, R_5
and R_6 have the above meanings] A general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
[In the formula, symbols R_1, R_2, R_3, R_4 and R_
5 has the above meaning] and a method for producing a polyene compound and a salt thereof.