JP2003238527A - Method for producing conjugated triene compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a conjugated triene compound. <P>SOLUTION: This method for producing the conjugated triene compound expressed by formula (2) (wherein a wavy line expresses that the stereochemistry of a double bond to which OH bonds, is any of a E-form, Z-form or a mixture of E/Z) is characterized by performing a reaction of a sulfone derivative expressed by formula (1) [wherein, Ar is an aryl which may have a substituting group; R is H, or a blocking group for hydroxy; and a wavy line is the same as in formula (2)] with a base. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a conjugated triene compound which is an important intermediate of retinoids and carotenoid derivatives which are pharmaceuticals, feed additives and food additives.

[0002]

2. Description of the Related Art As shown in Japanese Patent Application Laid-Open No. 11-222479, the present inventors have identified sulfones and C10 alcohols (geraniol, etc.) represented by the following general formula (3). ) Has been found, a sulfone derivative which is an important intermediate of vitamin A by a coupling reaction with allyl halides derived from the above), and the development of a more excellent production method has been desired.

[0003]

Under these circumstances, the inventors of the present invention have conducted extensive studies in order to solve the above-mentioned problems, and as a result, the sulfone represented by the following general formula (3), which is a raw material that can be easily purified. A conjugated triene compound (2), which is an important intermediate for retinoid and carotenoid derivatives, can be easily prepared by reacting a sulfone derivative (1) that can be easily derived from allyl halides represented by the following general formula (4) with a base. The inventors have found that they can be manufactured according to the present invention and have reached the present invention. That is, the present invention has the general formula (1) (In the formula, Ar is an aryl group which may have a substituent,
R represents a hydrogen atom or a hydroxyl-protecting group, and the wavy line represents the E-form, Z-form, or E / Z mixture in which the steric structure of the double bond to which it is bonded. ) A general formula (2) characterized by reacting a sulfone derivative represented by (In the formula, the wavy line has the same meaning as described above.) The present invention provides a method for producing a conjugated triene compound.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The conjugated triene compound (2) can be obtained by reacting the sulfone derivative (1) with a base.

R of the sulfone derivative represented by the general formula (1) used in the present invention represents a hydrogen atom or a hydroxyl-protecting group, and examples of the hydroxyl-protecting group include formyl, acetyl, ethoxyacetyl, fluoroacetyl,
Difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl,
Propionyl, 2-chloropropionyl, 3-chloropropionyl, butyryl, 2-chlorobutyryl, 3-chlorobutyryl, 4-chlorobutyryl, 2-methylbutyryl, 2-ethylbutyryl, valeryl, 2-methylvaleryl, 4-methylvaleryl, hexanoyl, isobutyryl, isovaleryl, Pivaloyl, benzoyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o-hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxybenzoyl, o-acetoxybenzoyl, o-methoxybenzoyl, m-methoxybenzoyl, p -Acyl group such as methoxybenzoyl and p-nitrobenzoyl, silyl such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl , Tetrahydropyranyl,
Alkoxymethyl group such as methoxymethyl, methoxyethoxymethyl, 1-ethoxyethyl, benzyl group, p-
An aralkyl group such as a methoxybenzyl group, a t-butyl group,
Trityl group, haloalkoxycarbonyl group such as 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl group and the like can be mentioned. Usually, acyl group is preferable,
An acetyl group is more preferably used.

Ar in the sulfone derivative represented by the general formula (1) represents an aryl group which may have a substituent, and examples of the aryl group include a phenyl group and a naphthyl group, and the substituent is C1. To C5 straight chain or branched alkyl group, C1 to C5 straight chain or branched alkoxy group, halogen atom, nitro group and the like. Specific examples of the substituent Ar include phenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-.
Chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-
Examples thereof include iodophenyl, p-iodophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl and the like.

Examples of the base used in the above reaction include alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal amides, and the like. Specifically, as alkali metal hydroxides, Is
Examples of alkali metal hydrides such as lithium hydroxide, sodium hydroxide and potassium hydroxide include sodium hydride and potassium hydride, and examples of alkali metal alkoxides include sodium t-broxide and potassium t-butoxide. Examples thereof include sodium methoxide and potassium methoxide, and examples of the alkali metal amide include sodium amide and potassium amide. In particular, an alkali metal hydroxide is preferably used. Further, the shape is preferably fine powder. The amount used is usually in the range of about 2 to 20 times, preferably about 3 to 15 times the mol of the sulfone derivative represented by the general formula (1).

The above reaction proceeds even with a base alone, but a lower alcohol or a phase transfer catalyst may be added to further accelerate the reaction.

Examples of the lower alcohol used in the above reaction include methanol, ethanol, i-propyl alcohol, s-butyl alcohol, t-butyl alcohol, ethylene glycol and the like. The amount used is usually, based on the sulfone derivative represented by the general formula (1),
It is about 0.1 to 3 mol times.

Examples of the phase transfer catalyst used in the above reaction include quaternary ammonium salts, quaternary phosphonium salts, sulfonium salts and the like, and preferably quaternary ammonium salts. As the quaternary ammonium salt, for example, tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrapentylammonium chloride, tetrahexylammonium chloride, tetraheptylammonium chloride, tetraoctylammonium chloride, chloride Trioctylmethylammonium, tetradecylammonium chloride, tridecylmethylammonium chloride, didecyldimethylammonium chloride, tetradodecylammonium chloride, tridodecylmethylammonium chloride, didodecyldimethylammonium chloride, dodecyltrimethylammonium chloride, dodecyltriethylammonium chloride, chloride Tetrahexadecyl ammonium,
Hexadecyltrimethylammonium chloride, hexadecyldimethylethylammonium chloride, tetraoctadecylammonium chloride, octadecyltrimethylammonium chloride, octadecyltriethylammonium chloride,
Benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, 1-methylpyridinium chloride, 1-hexadecylpyridinium chloride, 1,4-dimethylpyridinium chloride, trimethylcyclopropylammonium chloride or their chloride salts, Examples thereof include corresponding bromide salts, iodide salts, compounds converted into hydrogen sulfate, and the like.

Examples of the quaternary phosphonium salt include, for example,
Tributylmethylphosphonium chloride, triethylmethylphosphonium chloride, methyltriphenoxyphosphonium chloride, butyltriphenylphosphonium chloride, tetrabutylphosphonium chloride, benzyltriphenylphosphonium chloride, tetraoctylphosphonium chloride, hexadecyltrimethylphosphonium chloride, hexadecyltributylphosphonium chloride, Hexadecyldimethylethylphosphonium chloride, tetraphenylphosphonium chloride, or these chloride salts are the corresponding bromide salts,
Examples thereof include compounds that have become iodide salts.

Examples of the sulfonium salt include benzylmethylethylsulfonium chloride, benzyldimethylsulfonium chloride, benzyldiethylsulfonium chloride,
Examples thereof include dibutyl methyl sulfonium chloride, trimethyl sulfonium chloride, triethyl sulfonium chloride, tributyl sulfonium chloride, and compounds in which these chloride salts are converted into corresponding bromide salts and iodide salts.

Particularly, a quaternary ammonium salt is preferably used.

The amount of the phase transfer catalyst used is usually about 0.01 to 0.2 mol times, preferably about 0.02 to 0.1 mol times, relative to the sulfone derivative (1).

In the above reaction, an organic solvent is usually used, and examples of such a solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and anisole, n-hexane,
Hydrocarbon solvents such as cyclohexane, n-pentane, toluene, xylene, acetonitrile, N, N-dimethylformamide, hexamethylphosphoric triamide,
Aprotic polar solvents such as sulfolane, 1,3-dimethyl-2-imidazolidinone and 1-methyl-2-pyrrolidinone can be mentioned.

The reaction temperature is usually from -30 ° C to the boiling point of the solvent used, preferably from -10 to 50 ° C. The reaction time varies depending on the reaction temperature, but is usually in the range of about 1 to 48 hours.

After the reaction, the conjugated triene compound (2) can be obtained by a usual post-treatment operation. If necessary, it can be purified by crystallization, various chromatography and the like.

Since the conjugated triene compound is unstable, it is preferable to introduce a protecting group into the hydroxyl group to form an ester by a conventional method.

The sulfone derivative represented by the general formula (1) includes the sulfone represented by the general formula (3) and the general formula (4).
It can be obtained by reacting with an allyl halide derivative represented by

Here, the sulfone (3) is, for example, Che
According to the method described in m. Lett. 479 (1975), the allyl halide derivative (4) can be prepared according to, for example, US Pat.
It can be conveniently produced from isoprene in two steps by the method described in the specification.

Examples of the base used in the above reaction include alkyllithium, alkali metal alkoxide, alkali metal amide, and alkali metal hydride.
Specifically, for example, n-butyl lithium, s-butyl lithium, t-butyl lithium, sodium methoxide,
Potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, sodium t-amylate, potassium t-amylate, lithium amide, potassium amide , Sodium amide, lithium diisopropylamide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodium hydride, potassium hydride, lithium hydride and the like. These are, for example, sodium t
-Two or more kinds of bases may be used in combination such as a combination of butoxide and sodium hydride. For example, sodium t-butoxide may be produced from t-butanol and sodium hydride in a system, or diisopropyl may be used. The above-described bases may be used by being produced in the system from the respective raw material compounds, such as producing lithium diisopropylamide from the amine and n-butyllithium in the system. The amount of such a base used is usually about 0.5 to 3 mol times the sulfone (3).

When an alkali metal hydride is used as the base, a compound having active hydrogen can be added as an additive. Examples of the compound having active hydrogen include alcohols, amines, sulfones and sulfoxides, and specific examples include n-butyl alcohol and s-.
Examples thereof include butyl alcohol, t-butyl alcohol, t-amyl alcohol, aniline, diisopropylamine, dimethyl sulfone and dimethyl sulfoxide. The amount of such an additive to be used is usually about 0.1 to 3 mol times the sulfone (3), but a solvent amount may be used. These may be used alone or in combination of two or more. Further, as an anion activator, a compound having a coordination property with an alkali metal, for example, crown ethers or tetramethylethylenediamine may be added, and as an allyl halide activator, halogen exchange is induced. A compound such as an alkali metal iodide or tetraalkylammonium iodide may be added.

The above reaction is usually carried out in an organic solvent, and the solvent used is acetonitrile, N, N-
Dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, sulfolane, 1,3-
Dimethyl-2-imidazolidinone, aprotic polar solvent such as 1-methyl-2-pyrrolidinone, diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, anisole, diglyme, triglyme,
Examples thereof include ether solvents such as tetraglyme, alcohol solvents such as t-butanol, and hydrocarbon solvents such as n-hexane, cyclohexane, n-pentane, benzene, toluene and xylene. These may be used alone or as a mixed solvent of two or more kinds. Further, it is desirable to select an optimum solvent depending on the type of base used.

Usually, the reaction temperature can be arbitrarily selected within the range from -78 ° C to the boiling point of the solvent, but it is desirable to select the optimum reaction temperature depending on the starting compound, the base and the solvent used. When the base used is a type that generates hydrogen ions from the substrate by an equilibrium reaction and generates anions (for example, alkali metal alkoxides), increase the temperature of anionization (reaction between the base and sulfones (3)). The yield can be improved by setting the reaction temperature with the allyl halide derivative (4) to be low. The reaction time varies depending on various conditions such as the raw material compound used, the base, the solvent and the reaction temperature, but it is usually in the range of about 5 minutes to 24 hours.

The reaction is preferably carried out under non-oxygen conditions, preferably in an inert gas (nitrogen, argon) atmosphere, and it is desirable that the solvent used is sufficiently degassed. If a stabilizer such as 3,5-di-t-butyl-4-hydroxytoluene (BHT), 2- & 3-t-butyl-4-hydroxyanisole (BHA), vitamin E or ethoxyquin is added as an antioxidant. More preferable. After the reaction, the sulfone derivative (1) can be produced by an ordinary post-treatment such as extraction, washing, crystallization and various chromatography operations.

The conjugated triene compound represented by the general formula (2) obtained in the present invention is obtained by halogenating a hydroxyl group by a conventional method and then, J.Org.Chem., Vol.41, No.20 (1976) 3287.
Vitamin A can be induced by the method described in 1.

[0027]

Thus, according to the method of the present invention, important intermediates of retinoids and carotenoid derivatives in the fields of medicine, feed additives, food additives, etc. can be advantageously produced.

[0028]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 Compound (I) 421.1 mg (1.0 mmo)
l), 881.3 mg (15.0 mmol) of finely powdered potassium hydroxide,
Tetrabutylammonium hydrogen sulfate 34.0 mg (0.1 mmol)
Was charged, and the atmosphere was replaced with nitrogen under reduced pressure.
The mixture was charged and stirred at 0 ° C. Furthermore, methanol 34.0 mg (2 mmo
l) was added dropwise at the same temperature and stirred for 1 hour. After the reaction, the mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer is a saturated aqueous sodium hydrogen carbonate solution,
The extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product (II) as a yellow oil. The obtained crude product was dissolved in toluene 4 ml, and pyridine 118.6 mg (1.5 mmol), 4-dimethylaminopyridine 8.4 mg (0.05 mmol), acetic anhydride 153.1 mg (1.5 mmol).
Were sequentially added at 0 ° C. at room temperature, and the mixture was stirred at the same temperature for 1 hr. After the reaction, the mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product (III) as a yellow oil. The obtained crude product was quantified by liquid chromatography to find that the compound (III)
The yield was 91.2%.

(Example 2) 421.1 mg (1.0 mmo) of compound (I)
l), 881.3 mg (15.0 mmol) of finely powdered potassium hydroxide,
Tetrabutylammonium hydrogen sulfate 34.0 mg (0.1 mmol)
Was charged, and the atmosphere was replaced with nitrogen under reduced pressure.
The mixture was charged at 0 ° C and stirred for 5 hours. After the reaction, the mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product (II) as a yellow oil. The obtained crude product was dissolved in 4 ml of toluene, and 118.6 mg (1.5 mmol) of pyridine and 4-dimethylaminopyridine 8.
4 mg (0.05 mmol) and acetic anhydride 153.1 mg (1.5 mmol) were sequentially added at 0 ° C. at room temperature, and the mixture was stirred at the same temperature for 1 hour. After the reaction, the mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer is a saturated ammonium chloride aqueous solution,
The product was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product (III) as a yellow oil. The obtained crude product was quantified by liquid chromatography, and the yield of compound (III) was 55.
It was 4%.

The structural formulas of the compounds of the examples are shown below.

(Reference example) A solution of 224 mg (2 mmol) of potassium t-butoxide dissolved in 6 ml of DMF was cooled to -60 ° C, and 585 mg of sulfone (I) (2 mmo
A DMF (4 ml) solution of 1) was added dropwise over 20 seconds, and after the addition, the temperature was kept at the same temperature for 30 minutes. Then, allyl halide (II) (9
6) A solution of 215 mg (1 mmol) in DMF (4 ml) was added dropwise at the same temperature over 5 minutes, and the mixture was stirred for 3 hours. After the reaction, the mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product as a yellow oil. When the resulting crude product was quantified by high performance liquid chromatography, sulfone derivatives (III) and (IV) were obtained in yields of 71.2% and 15.4%, respectively.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4H006 AA02 AC26 AC41 BA51 BA65                       BB14 BB15 BB20 BB21 BB22                       BB25 BE10 UA12 UC12                 4H039 CA29 CA60

Claims (8)

[Claims] 1. A general formula (1) (In the formula, Ar is an aryl group which may have a substituent,
R represents a hydrogen atom or a hydroxyl-protecting group, and the wavy line represents the E-form, Z-form, or E / Z mixture in which the steric structure of the double bond to which it is bonded. ) A general formula (2) characterized by reacting a sulfone derivative represented by (In the formula, the wavy line has the same meaning as described above.) A method for producing a conjugated triene compound. 2. The production method according to claim 1, wherein the base is an alkali metal hydroxide. 3. The method according to claim 2, wherein the alkali metal hydroxide is potassium hydroxide. 4. The method according to claim 2, wherein the alkali metal hydroxide is in the form of fine powder. 5. The production method according to claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst and / or a lower alcohol. 6. The method according to claim 5, wherein the phase transfer catalyst is a quaternary ammonium salt. 7. The production method according to claim 1, wherein R is an acyl group. 8. The production method according to claim 1, wherein R is an acetyl group.