WO2003043977A1

WO2003043977A1 - Process for preparation of geranyl aryl sulfones

Info

Publication number: WO2003043977A1
Application number: PCT/JP2002/011904
Authority: WO
Inventors: Shinzo Seko; Noriyuki Doi
Original assignee: Sumitomo Chemical Company, Limited
Priority date: 2001-11-19
Filing date: 2002-11-15
Publication date: 2003-05-30
Also published as: TW200300409A

Abstract

A process for the preparation of geranyl aryl sulfones represented by the general formula (4): (4) [wherein Ar is optionally substituted aryl; and the wavy line represents either of E/Z geometrical isomers or a mixture of both], characterized by reacting an allyl halide represented by the general formula (3): (3) [wherein X is halogeno; and the wavy line is as defined above] with an arylsulfinic acid salt in the presence of a phase-transfer catalyst and an inorganic salt.

Description

Description Manufacturing method of geranyl aryl sulfone Technical field

The present invention relates to a method for producing geranylaryl sulfone, which is a raw material for vitamin A derivatives and various terpene compounds used as pharmaceuticals, feed additives, food additives, and the like. Background art

The present inventors have found that arylsulfonyl chloride, which is already less expensive than arylsulfinate, is reduced in an aqueous solvent to produce arylsulfinate in the system, and without isolation, It has been found that by adding the aryl halide compound represented by (3), geranylyaryl sulfone represented by the following formula (4) can be obtained in one pot (Japanese Patent Application Laid-Open No. 2001-218386). No. 0). This method gives geranyl aryl sulfone (4), even if the aqueous solvent used in the reduction step of aryl aryl sulfoxide is present during the subsequent reaction with aryl halide compound (3). However, it was necessary to further improve the yield from an industrial and economic viewpoint.

The present inventors have conducted intensive studies to achieve a further improvement in the yield, and as a result, reacted the arylsulfinate with the aryl halide compound (3) in the presence of a phase transfer catalyst and an inorganic salt. As a result, they have found that the yield is improved, and have completed the present invention. Disclosure of the invention

That is, the present invention

1. Equation (3):

[In the formula, X represents a halogen atom, and a wavy line represents either one of the EZZ geometric isomers or a mixture thereof.]

An aryl halide compound represented by the formula (2):

A r S0 ₂ M (2)

[Wherein, Ar represents an aryl group which may have a substituent, and M represents sodium or potassium]

Wherein an arylsulfinate salt represented by the formula (4) is reacted in the presence of a phase transfer catalyst and an inorganic salt:

( ⁴ )

[Wherein, Ar and wavy lines are as defined above]

A method for producing geranyl aryl sulfone represented by, and

2. An arylyl sulfide compound represented by the formula (3) and an aryl sulfinate represented by the formula (2) are

a) a phase transfer catalyst selected from a quaternary ammonium iodide salt, a quaternary phosphonium iodide salt or a sulfonium iodide salt, and an inorganic salt, or

b) Quaternary ammonium chloride, bromide or hydrogen sulphate, quaternary phosphonium salt, bromide or hydrogen sulphate or sulfonium chloride, bromide or hydrogen sulphate A phase transfer catalyst selected from salts, alkali metal halides and inorganic salts,

Reacting in the coexistence of geranyaryl aryl sulfone represented by formula (4), and

3. The aryl sulfinate represented by the formula (2) is converted to the formula (1):

Ar S0 ₂ C 1 (1)

[Wherein, Ar represents an aryl group which may have a substituent]

And a method for producing a geranyl aryl sulfone represented by the formula (4) as described in the above 1 or 2, which is an aryl sulfinate obtained by reducing the aryl sulfoyluclide obtained by the formula . BEST MODE FOR CARRYING OUT THE INVENTION

The substituent Ar in the compounds represented by the formulas (1), (2) and (4) of the present invention represents an aryl group which may have a substituent, and the aryl group is a phenyl group or a naphthyl group. and the like, as the substituent, Ji厂C ₅ or branched al kill group (e.g., methyl, Echiru, n - propyl, i- propyl, n- butyl, t-heptyl, n- pentyl group ), A C ^ Cs linear or branched alkoxy group (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n-butyloxy, t-butyloxy, n-, t-, neo-pentyloxy) Group), a halogen atom, a nitro group, and the like. More specifically, phenyl, naphthyl, 0-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-clohpheninole, m-clohfener Nore, p-black mouth, o-bromophenyl, m-bromophenyl, p-bromophene, 0-eodophenyl, m-edofenore, p-eodofenore, 0-fuenoreno, m— Examples include fuoreno-rofenore, p-funore-norofenore, o-nitropheninole, m-nitropheninole, and p-nitrophenyl.

Further, the substituent X in the aryl halide compound represented by the formula (3) represents a halogen atom, and specific examples include a chlorine atom, a bromine atom and an iodine atom.

The arylsulfinic acid salt used in the present invention can be obtained, for example, by reducing an arylsulfuric acid mouth chloride represented by the formula (1). The reduction reaction is carried out in the presence of a reducing agent and a base. It is preferable to carry out in an aqueous solvent. As the reducing agent, a sulfite or a hydrogen sulfite is preferable, and specific examples thereof include sodium sulfite, potassium sulfite, sodium hydrogen sulfite, and hydrogen sulfite. The amount used is usually in the range of 1 to 2.5 mol times, preferably about 102 to 2.00 mol times, relative to arylsulfonyl chloride (1).

In the above reaction, when the pH is on the acidic side, the free form of sulfinic acid produces thiosulfonate by-produced by the disproportionation reaction, so that the yield decreases. In order to avoid this, it is preferable to keep a base at about pH 8 or more by coexisting a base. The coexisting base is preferably an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, and the like. Specifically, sodium hydroxide, potassium hydroxide , Sodium carbonate, carbon dioxide lime, sodium hydrogen carbonate, hydrogen hydride, etc. The amount used is usually in the range of about 1 to 5 moles, preferably about 1.02 to 2.50 moles, per mole of arylsulfoylc mouth ride (1). The reaction temperature is usually in the range of 0 ° C to 100 ° C, but preferably in the range of about 20 ° C to 70 ° C. The reaction time is usually in the range of 1 hour to 24 hours.

After completion of the reaction, the reaction mixture may be isolated by concentration or the like. The geranyl aryl sulfone represented by is obtained. The amount of the arylhalide compound (3) to be added is usually in the range of about 0.3 to 1.2 mol times, preferably about 0.7 to 1 mol times, relative to the arylsulfoylc mouth ride (1). You.

The reaction is preferably carried out in the presence of a phase transfer catalyst, in the presence of an inorganic salt or the like, and in a water-hydrophobic organic solvent two-phase system or only an aqueous solvent.

When performed in a two-phase system, the hydrophobic organic solvent includes hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene, 1-chlorobutane, 1,2-dichloroethane, Halogen solvents such as benzene, onoletodichlorobenzene, trifluoromethylbenzene, etc .; carbonyl solvents such as methyl isobutyl ketone, methyl ethyl ketone, methyl acetate, and ethyl acetate; etc. And ether solvents such as methyl t-butyl ether.

Examples of the phase transfer catalyst used include quaternary ammonium salts, quaternary phosphonium salts, and sulfonium salts. Examples of quaternary ammonium salts include tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrapentylammonium chloride, tetrahexylammonium chloride, and tetrahexylammonium chloride. Tetraheptylammonium chloride, Tetraoctylammonium chloride, Trioctylmethylammonium chloride, Tetradecylammonium chloride, Tridecylmethylammonium chloride, Didecyldimime chloride, Diammonium chloride, Tetradodecyl chloride Ammonium, Shiodii Tridodecylmethylammonium, Didodecyldimethylammonium chloride, Dodecinoletrimethyl chloride Ammonia, Hidodedecyltriethylammonium, Hidanitetradecyltrimethylammonium, Hidanitetratetrahexadecylammonium, Hidanihexadecyltrimethylammonium, Hexadecyldimethylethyl chloride Ammonia, tetraoctadecylammonium chloride, octadecyltrimethylammonium chloride, octadecyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride Ammene, benzyltributynoleammonium chloride, shiridani 1-methylpyridinium chloride, 1-hexadecylpyridinium chloride, 1,4-dimethylpyridinium chloride, salt Trimethylcyclopropylammonium or their chloride salts are the corresponding bromide or iodide salts, respectively. Or a compound that has become a hydrogen sulfate salt.

Examples of the quaternary phosphonium salts include, for example, Shiridani tributylmethylphosphonium, Shiridani triethylmethylphosphonium, Shiridani methyltriphenoxyphosphonium, Shiridani butyltriphenylphosphonium, and Salt Tetrabutylphosphonium chloride, benzyltriphenylphosphonium chloride, tetraoctylphosphochloride chloride, hexadecyltrimethylphosphonium chloride, hexadecyltributylphosphonium chloride, chloride Compounds obtained by converting the oxadecyldimethylethylphosphonium chloride, the tetraphenylphosphonium chloride, or the chloride salt thereof into the corresponding bromide salt, iodide salt, or hydrogen sulfate salt, respectively. Can be

Examples of the sulfonium salt include, for example, sodium chloride benzylmethylethylsulfonium, benzyldimethylsulfonyl chloride, sodium benzylbenzylethylsulfonium, dibutylmethylsulfonium chloride, trimethylsulfonyl chloride And triethylsulfonium chloride, tributylsulfonium chloride, or compounds in which these chloride salts have been converted to the corresponding bromide, iodide, or hydrogen sulfate salts, respectively.

Among these phase transfer catalysts, iodide salts are preferred, and quaternary ammonium iodide is particularly preferred. When a hydrogen sulfate salt, chloride salt or bromide salt is used, it is preferable that an alkali metal iodide such as sodium iodide or potassium iodide coexist.

The amounts of the phase transfer catalyst and the alkali metal iodide used are It is usually in the range of about 0.001 to 0.2 mol, preferably about 0.01 to 0.1 mol, per mol of the halide compound (3).

In the present invention, the addition of an inorganic salt is effective for reducing the amount of use of a phase transfer catalyst, particularly expensive quaternary ammonium iodide, or for improving the reactivity.

Examples of such inorganic salts include alkali metal or alkaline earth metal salt salts or bromide salts. Specifically, for example, sodium chloride, sodium chloride, sodium bromide, odor, etc. Potassium chloride, calcium chloride, calcium bromide, Shiridani magnesium, magnesium bromide and the like. The amount of strong inorganic salt used also depends on the amount of aqueous solvent used in the previous step. The content is usually in the range of 20 to 300% by weight, preferably 50 to 200% by weight, based on the aryl halide compound (3).

The reaction temperature is usually in the range of 30 ° C to 110 ° C, preferably in the range of about 50 ° C to 100 ° C. The reaction time is usually in the range of 1 hour to 24 hours. After the reaction, the obtained geranylaryl sulfone (4) can be isolated and purified by extraction, washing, crystallization, various types of chromatography and the like.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1

400 mg (2.1 mmol) of p-toluenesulfuric acid mouth slide, 300 mg (2.3 mmol) of sodium sulfite and 244 mg (2.3 mmol) of sodium carbonate were suspended in 2 ml of water and stirred at 50 for 2 hours. . Tsugire, in, the reaction mixture ® © tetrabutyl ammonium Niu arm 14.8 mg (0.04 mmol, 2 mol ^_0/0) and Shioi匕Natoriumu 345mg was added, further geranyl chloride (purity 95. 5%) 361 mg ( 2.0 mmol) and stirred at 96 for 4 hours. After the reaction was completed, a small amount of water was added to the reaction solution, extracted with toluene, and analyzed by gas chromatography. The yield of geranyl p-tolylsulfone was 92% (vs. geranyl chloride). there were.

Comparative Example 1

The reaction was carried out in the same manner as in Example 1 except that sodium salt was not added, and analysis by gas chromatography revealed that the yield of geranyl P-tolylsulfone was 78% (vs. geralyl chloride).

Examples 2 to 4

The reaction was carried out in the same manner as in Example 1 except that the amount of sodium chloride was changed to 69 Omg and the amount of tetrabutylammonium iodide was changed as shown in Table 1 below, and analyzed by gas chromatography. Geranyl p_tolylsulfone was obtained in a yield like 1.

Example 5

40-mg (2.1 mmol) of p-toluenesulfuric acid mouth water, 300 mg (2.3 mmol) of sodium sulfite and 244 mg (2.3 mmol) of sodium carbonate were suspended in 2 ml of water, and the suspension was added at 50 Stirred for hours. Then, the reaction mixture bromide tetrabutylammonium Niu arm 12.9tng (0 · 04 mmol, 2 mol ^_0/0), sodium iodide 15 mg (0. 1 mmol, 5 mol ^_0/0) and salts Ihinatoriumu 69 Om g Was added, and 36 lmg (2.0 millimoles) of gelauruku mouth ride (purity: 95.5%) was added, followed by stirring at 96 ° C for 3 hours. After completion of the reaction, a small amount of water was added to the reaction solution, extracted with toluene, and analyzed by gas chromatography. The yield of geraninole P-tolylsulfone was 93% (vs. geranyl chloride).

Example 6

The reaction was carried out in the same manner as in Example 5 except that the amount of tetrabutylammonium bromide was changed to 32.2 mg (0.1 mmol, 5 mol%). As a result, the yield of Gerajeru p-tolylsulfone was 96% (vs. geranyl chloride).

Example 7

The reaction was carried out in the same manner as in Example 6 except that sodium chloride was not added, and analyzed by gas chromatography, the yield of geranyl p-tolylsulfone was 86%.

(Vs. geranyl chloride).

Example 8

The reaction was carried out in the same manner as in Example 5 except that 13.6 mg (0.04 mmol, 2 mol%) of tetrabutylammonium hydrogen sulfate was added instead of tetrabutylammonium bromide, and analyzed by gas chromatography. The yield of geraninole p-tolylsnolefone was 92% (vs. geranyl chloride).

Example 9

400 mg (2.1 mmol) of p-toluenesulfonyl chloride, 300 mg (2.3 mmol) of sodium sulfite and 244 mg (2.3 mmol) of sodium carbonate were suspended in 2 ml of water and stirred at 50 ° C. for 2 hours. Then, the reaction mixture ® © tetrabutyl ammonium Niu arm 7.5 mg (0.02 mmol, 1 mole ^_0/0) and added salt sodium 776 mg, further galley Nino Les chloride (purity 89%) 388 mg (2.0 mmol) A solution dissolved in 2 ml of methyl isobutyl ketone was added, and the mixture was stirred at 85 to 90 ° C for 3 hours. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the obtained oil was analyzed by gas chromatography. The yield of geranyl p-tolylsulfone was 97% (vs. geranyl chloride).

Comparative Example 2

The reaction was carried out in the same manner as in Example 9 except that sodium chloride was not added, and analysis by gas chromatography revealed that the yield of geranyl p-tolylsulfone was 71% (vs. gelurauc-mouth).

Example 10

400 mg (2.1 mmol) of p-toluenesulfoyluc mouth ride, sodium sulfite 300 mg (2.3 mmol) of platinum and 244 mg (2.3 mmol) of sodium carbonate were suspended in 2 ml of water and stirred at 50 ° C for 2 hours. Tsugire, in, ® © tetrabutyl ammonium in the reaction mixture - © beam 22. 2 mg (0.06 mmol, 3 mol ^_0/0) and the chloride Natoriumu 69 Omg addition, further Gerayuruku port chloride (purity 95.5%) 36 1 mg (2.0 mmol) dissolved in 2 ml of toluene, 96. The mixture was stirred at C for 3 hours. After the reaction was completed, a small amount of water was added to the reaction solution, extracted with toluene, and analyzed by gas chromatography. The yield of geraninole p-tolylsulfone was found to be

91% (vs. geranyl chloride). Industrial applicability

According to the method of the present invention, geranylyaryl sulfone (4) can be produced with a high yield from an inexpensive arylsulfoylc mouth ride in one pot. This method is industrially advantageous because inexpensive raw materials can be used, and the amount of phase transfer catalysts, especially expensive quaternary ammonium iodide, can be reduced, and the product can be obtained in a high yield using only an aqueous solvent. It is a way.

Claims

The scope of the claims

1. Equation (3):

[In the formula, X represents a halogen atom, and a wavy line represents one of the EZZ geometric isomers or a mixture thereof.]

An aryl halide compound represented by the formula (2):

A r SO ₂ M (2)

[Wherein, Ar and wavy lines are as defined above]

A method for producing geranyl aryl sulfone represented by the formula:

2. The arylyl sulfide compound represented by the formula (3) and the aryl sulfinate salt represented by the formula (2) are

b) From quaternary ammonium chloride, bromide or hydrogen sulphate, quaternary phosphonium chloride, bromide or hydrogen sulphate or sulfonium chloride, bromide or hydrogen sulphate Selected phase transfer catalyst, lithium metal iodide and inorganic salt,

2. The method for producing geranyaryl aryl sulfone represented by the formula (4) according to claim 1, wherein the reaction is carried out in the presence of:

A r S0 ₂ C 1 (1) Wherein Ar represents an aryl group which may have a substituent, wherein the aryl aryl sulfinic acid salt is obtained by reducing an aryl sulfoyl chloride. A method for producing geranylaryl sulfone represented by the formula (4) according to 1 or 2.

4. Reduction of arylsulfonyl chloride represented by the formula (1) to obtain arylsulfinate represented by the formula (2), and isolation of the arylsulfinate represented by the formula (3) without isolation. 4. The method for producing geranyl aryl sulfone represented by the formula (4) according to claim 3, wherein the reaction is carried out.

5. The method for producing geranyl aryl sulfone according to any one of claims 1 to 4, which is performed in an aqueous solvent.

6. The method for producing geranyl aryl sulfone according to any one of claims 1 to 4, which is performed in a two-phase system of water and a hydrophobic organic solvent.

7. The reaction of reducing an arylsulfonyl chloride represented by the formula (1) to obtain an arylsulfinate represented by the formula (2) is performed in water in the presence of a reducing agent and a base. The method for producing geranyl aryl sulfone as described above.

8. Formula (5) as a reducing agent:

M ₂ SO ₃ (5)

[Where M represents a sodium or force stream]

Or a sulfite represented by the formula (6):

MHSO ₃ (6)

[Where M represents a sodium or force stream]

The method for producing geranyl aryl sulfone according to claim 6, wherein a bisulfite represented by the following formula is used.

9. The method for producing geranylyaryl sulfone according to claim 7, wherein the base is an alkali metal carbonate or an alkali metal bicarbonate.

10. The method for producing geranyl aryl sulfone according to any one of claims 1 to 9, wherein the inorganic salt is a salt or bromide of an alkali metal or an alkaline earth metal.

11. The method of claim 10, wherein the salt of the metal is sodium salt.