JPH10251219A - Production of arylvinylsulfone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an arylvinylsulfone useful as a drug intermediate by reacting a specific β-haloethylarylsulfonic acid with an alkali metal salt in the presence of an amine. SOLUTION: A β-haloethylarylsulfonic acid of formula I (R<1> and R<2> are each H, a halogen, a lower alkyl, a lower alkoxy, nitro, etc.; X is a halogen) is reacted with an alkali metal salt [e.g. an alkali metal (hydrogen) carbonate such as potassium carbonate] of not less than 0.8 molar time as much as the amount of the β-haloethylarylsulfonic acid of formula I in terms of the alkali metal in the presence of an amine (e.g. secondary amine and tertiary amine, such as dimethylamine) of 0.005-0.5 molar time as much as the amount of the β-haloethylarylsulfonic acid of formula I at 0-150 deg.C, if necessary, in the presence of a hydrophobic organic solvent, optionally carrying out a crystallizing treatment of the produced compound to separate the objective compound to industrially and advantageously provide the objective compound of formula II in the method for producing arylvinylsulfone.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing aryl vinyl sulfone.

[0002]

2. Description of the Related Art Aryl vinyl sulfone is a compound widely used in organic synthesis reactions as an equivalent of ethylene, and is also an important compound as a pharmaceutical intermediate.

[0003] As a method for producing such aryl vinyl sulfone, for example, a method of treating β-haloethylaryl sulfone with a base [J. Org. Chem. , 58 , 45
06 (1993); Chem. Soc. , 1754
(1949) etc. are known, but all require 1 mol or more of triethylamine to β-haloethylarylsulfone as a base, so that the load of nitrogen in wastewater is large, and industrial production The method had problems.

[0004] Further, when the amount of triethylamine used is reduced, there is a problem that the yield of the target aryl vinyl sulfone is reduced.

[0005]

SUMMARY OF THE INVENTION Accordingly, the present inventors
As a result of intensive studies to develop a method capable of industrially producing arylvinylsulfone from β-haloethylarylsulfone, the use of an amine without using an alkali metal salt without lowering the yield was achieved by using an alkali metal salt together with the amine. Have been found, and the present invention has been achieved.

[0006]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group,
Amino group, lower alkylamino group, di (lower alkyl)
X represents an amino group, and X represents a halogen atom. Wherein β-haloethylarylsulfone represented by formula (1) is reacted with an alkali metal salt in the presence of an amine. (In the formula, R ¹ and R ² each have the same meaning as described above.)
And a method for producing an aryl vinyl sulfone represented by the formula:

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the β-haloethylarylsulfone represented by the general formula (1), the substituents R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a lower alkyl group,
It represents a lower alkoxy group, a nitro group, an amino group, a lower alkylamino group or a di (lower alkyl) amino group, and the substituent X represents a halogen atom.

The halogen atom in the substituents R ¹ and R ² is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the lower alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, an n-propyl group. A linear or branched alkyl group having 1 to 6 carbon atoms such as a butyl group, an n-pentyl group, an i-propyl group, an i-butyl group, a sec-butyl group, a t-butyl group and a neopentyl group. As the lower alkoxy group, for example, methoxy group, ethoxy group,
straight or branched carbon atom 1 such as n-propoxy group, n-butoxy group, n-pentoxy group, i-propoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, neopentoxy group, etc. To 6 alkoxy groups.

The lower alkylamino group is an amino group substituted with one lower alkyl group, and the lower alkyl group includes the same ones as described above. Examples of such a lower alkylamino group include a methylamino group, an ethylamino group and a t-butylamino group. The di (lower alkyl) amino group is an amino group substituted with two lower alkyl groups. Examples of the lower alkyl group include the same as those described above. Such di (lower alkyl) amino group includes dimethylamino. Group, methylethylamino group, diethylamino group, t-butylmethylamino group and the like.

[0010] Examples of the halogen atom represented by the substituent X include a chlorine atom, a bromine atom, an iodine atom and the like.

Examples of the β-haloethylarylsulfone include (β-chloroethylsulfonyl) benzene and 4-chloro-1- (β-chloroethylsulfonyl)
Benzene, 1- (β-chloroethylsulfonyl) -3,
4-dichlorobenzene, 4-bromo-1- (β-chloroethylsulfonyl) benzene, 1- (β-chloroethylsulfonyl) -4-fluorobenzene, 1- (β-chloroethylsulfonyl) -4-iodobenzene, 1- (β
-Chloroethylsulfonyl) -4-methylbenzene, 1
-(Β-chloroethylsulfonyl) -2,4-dimethylbenzene, 1- (β-chloroethylsulfonyl) -4-
Ethylbenzene, 1- (β-chloroethylsulfonyl)
-4-i-butylbenzene, 1- (β-chloroethylsulfonyl) -4-t-butylbenzene, 1- (β-chloroethylsulfonyl) -4-methoxybenzene, 1-
(Β-chloroethylsulfonyl) -3,4-dimethoxybenzene, 1- (β-chloroethylsulfonyl) -4-
t-butoxybenzene, 3- (β-chloroethylsulfonyl) aniline, 3- (β-chloroethylsulfonyl)
-N-methylaniline, 3- (β-chloroethylsulfonyl) -N-ethylaniline, 3- (β-chloroethylsulfonyl) -N, N-dimethylaniline, 3- (β-
Chloroethylsulfonyl) -N, N-diethylaniline, 1- (β-chloroethylsulfonyl) -3-nitrobenzene and the above compound wherein the β-chloroethylsulfonyl group is a β-bromoethylsulfonyl group or a β-iodoethylsulfonyl group And the like.

These β-haloethylarylsulfones are prepared, for example, by a method of oxidizing a sulfide compound obtained by reacting a thiophenol compound with 1,2-dihaloethane [J. Org. Chem. , 58 , 4506 (199
3)], a method of reacting a thiophenol compound with 2-chloroethanol, and then oxidizing a sulfide compound obtained by chlorination [J. Chem. Soc. , 175
4 (1949)] can be easily produced. The substituent on the aromatic ring may be introduced in some cases after obtaining the sulfone compound.

As a method for reacting the β-haloethylarylsulfone represented by the general formula (1) with an alkali metal salt in the presence of an amine, the β-haloethylarylsulfone, the alkali metal salt and the amine are simply used. What is necessary is just to mix. In such mixing, the mixing order of the three is not particularly limited, and for example, a method of adding an amine and an alkali metal salt to β-haloethylarylsulfone, a method of adding β-haloethylarylsulfone and an amine to an alkali metal salt And the like. Preferably, a method of adding an amine and an alkali metal salt to β-haloethylarylsulfone is employed. Such additions may be made continuously.

The mixing is preferably carried out in the presence of a hydrophobic organic solvent. Examples of such a solvent include ether solvents such as diethyl methane and diethyl ether, benzene, toluene, xylene, chlorobenzene, and the like.
Aromatic solvents such as dichlorobenzene, dichloromethane,
Hydrophobic organic solvents such as 1,2-dichloroethane, chloroform, halogenated hydrocarbon solvents such as carbon tetrachloride and the like, which are inert to the reaction and mixed solvents thereof, and the amount thereof used is β-haloethylarylsulfone. Usually 50
It is less than weight times.

The β-haloethylarylsulfone and the amine may be used as they are. However, the above-mentioned hydrophobic organic solvent is added in advance to either or both of the β-haloethylarylsulfone and the amine to form a solvent solution. Is also good.

The alkali metal salt is usually used as an aqueous solution. Examples of the alkali metal salt include an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate and the like. Salts are preferably used. As the alkali metal hydroxide, for example, sodium hydroxide, potassium hydroxide and the like,
As the alkali metal carbonate, for example, potassium carbonate, sodium carbonate, etc., as the alkali metal bicarbonate,
For example, potassium bicarbonate, sodium bicarbonate and the like can be mentioned, among which potassium carbonate is preferably used. Such alkali metal salts may be used alone or in combination of two or more.

The amount of the alkali metal salt used is usually 0.1 in terms of alkali metal relative to β-haloethylarylsulfone.
It may be at least 8 mole times, preferably 1 to 4 mole times.

Examples of the amine used in the present invention include primary amines, secondary amines, tertiary amines, heterocyclic amines, inorganic acid salts of the above-described amines, and quaternary ammonium salts. Amines, tertiary amines, inorganic salts of tertiary amines, and quaternary ammonium salts are preferably used.

Primary amines include, for example, propylamine, isobutylamine, benzylamine, allylamine, aniline and the like. Secondary amines include, for example, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, and the like. Examples of tertiary amines include pyrrolidine, piperidine, morpholine, N-methylaniline and the like, for example, trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, diisopropylethylamine, N, N-dimethylbenzylamine, 1,5-diazabicyclo [4.
3.0] none-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine,
Examples of N, N-dimethylaniline and N, N, N ', N'-tetramethylethylenediamine, and examples of the heterocyclic amine include pyridine.

Examples of the inorganic acid salts of the above-mentioned amines include the above-mentioned primary amine, secondary amine, tertiary amine, and heterocyclic amine hydrochloride, sulfate, and hydrogen bromide. Examples include amine hydrochloride, diethylamine hydrochloride, trimethylamine hydrochloride, triethylamine hydrochloride, triethylamine sulfate, and pyridine hydrochloride.

Examples of the quaternary ammonium salt include triethylbenzylammonium chloride, triethylbenzylammonium bromide, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium bromide. No.

These amines may be used alone or in combination of two or more. The amount of the amine is usually 0.1 to β-haloethylarylsulfone.
It is in the range of 005 to 0.5 mole times, preferably 0.01 to 0.3 mole times.

The reaction temperature is usually in the range of 0 to 150 ° C, preferably 10 to 100 ° C.

The reaction mixture obtained by reacting β-haloethylarylsulfone with an alkali metal salt in the presence of an amine as described above is subjected to liquid separation treatment, if necessary, by adding water, thereby containing arylvinylsulfone. A solution is obtained, and the arylvinylsulfone can be taken out by directly concentrating or crystallizing the solution.However, usually, the solution is washed by adding water or an acidic aqueous solution such as diluted hydrochloric acid or diluted sulfuric acid, and then concentrated. Alternatively, a crystallization treatment is performed. The taken-out aryl vinyl sulfone may be further purified by washing, recrystallization and the like.

When the aryl vinyl sulfone is taken out by the crystallization treatment, the solution containing the aryl vinyl sulfone may be subjected to the crystallization treatment as it is after the washing treatment, or may be obtained by distilling a part of the solvent from the solution after the washing treatment. The resulting concentrated solution may be subjected to crystallization treatment.

Examples of the crystallization treatment include cooling crystallization, evaporation crystallization, and a method of mixing a solution containing aryl vinyl sulfone with a solvent that does not substantially dissolve aryl vinyl sulfone (hereinafter referred to as poor solvent). But
A method of mixing the solution and the poor solvent is preferred.

The method of mixing the solution and the poor solvent may be either a method of adding a poor solvent to the solution or a method of adding the solvent to the poor solvent, but the latter method is preferred. Examples of the poor solvent include aliphatic hydrocarbon solvents such as hexane and heptane.The amount of the poor solvent is usually 100 times by weight or less, preferably 0.5% by weight, based on the aryl vinyl sulfone contained in the solution. ５０50 times by weight.

By mixing the solution containing the aryl vinyl sulfone with the poor solvent, the crystals of the aryl vinyl sulfone are usually precipitated. The crystals may be taken out as they are, but it is cooled to form more crystals of the aryl vinyl sulfone. It is preferable to precipitate and take out.

The aryl vinyl sulfone thus obtained is, for example, phenyl vinyl sulfone, (4-chlorophenyl) vinyl sulfone, (3,4-dichlorophenyl) vinyl sulfone, (4-bromophenyl) vinyl sulfone, (4-fluorophenyl) Vinyl sulfone,
(4-iodophenyl) vinylsulfone, (4-methylphenyl) vinylsulfone, (2,4-dimethylphenyl) vinylsulfone, (4-ethylphenyl) vinylsulfone, (4-i-butylphenyl) vinylsulfone,
(4-t-butylphenyl) vinylsulfone, (4-methoxyphenyl) vinylsulfone, (3,4-dimethoxyphenyl) vinylsulfone, (4-t-butoxyphenyl) vinylsulfone, (3-aminophenyl) vinylsulfone (3-methylaminophenyl) vinylsulfone, (3-ethylaminophenyl) vinylsulfone,
(3-dimethylaminophenyl) vinyl sulfone, (3
-Diethylaminophenyl) vinylsulfone, (3-nitrophenyl) vinylsulfone and the like.

[0030]

According to the method of the present invention, the amount of amine used can be reduced and arylvinylsulfone can be industrially and advantageously produced from β-haloethylarylsulfone in good yield.

[0031]

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

Example 1 40.9 g of (β-chloroethylsulfonyl) benzene
(200 mmol) dissolved in 100 g of toluene,
30.7 g of a 49% aqueous potassium carbonate solution (potassium carbonate 1
09 mmol) and 1.01 g of triethylamine (1
0 mmol), and the mixture was stirred and kept at 40 to 45 ° C for 3 hours. After the completion of the incubation, the reaction mass was washed once with 70 g of water, once with 35 g of a 5% aqueous sulfuric acid solution, and once with 35 g of water, and 33.1 g of phenylvinylsulfone was obtained by distilling off the solvent from the washed reaction mass. Yield 98.4%).

Example 2 55.6 g of a 20% aqueous sodium carbonate solution (105 mmol of sodium carbonate) in place of the 49% aqueous potassium carbonate solution
By operating in the same manner as in Example 1 except for using 30.6 g of phenylvinylsulfone (yield 91.0%).

EXAMPLE 3 1.50 g (10 mmol) of 1- (β-chloroethylsulfonyl) -3-nitrobenzene was added to 20 g of toluene, and 1.50 g of a 49% aqueous potassium carbonate solution (5.3 mmol of potassium carbonate) and 50% of triethylamine were added.
mg (0.5 mmol) was added and the mixture was stirred and kept at 40 ° C. for 2 hours. After completion of the heat retention, 10 g of water was added to the reaction mass, followed by liquid separation to obtain an organic phase and an aqueous phase. The aqueous phase was extracted with chloroform, and the obtained organic phase was combined with the previous organic phase, dried over magnesium sulfate, filtered with magnesium sulfate, and the solvent was distilled off from the obtained filtrate to give (3- 2.01 g of nitrophenyl) vinylsulfone (yield 94.3)
%).

Example 4 4.09 g of (β-chloroethylsulfonyl) benzene
(20 mmol) was added to 20 g of toluene.
3.00 g of 10% aqueous potassium carbonate solution (10.
6 mmol) and diisopropylethylamine 113
mg (0.88 mmol) was added, and the mixture was stirred and kept at 40 ° C. for 4 hours. After completion of the heat retention, 10 g of water was added to the reaction mass, followed by liquid separation to obtain an organic phase and an aqueous phase. The aqueous phase was extracted with chloroform, and the obtained organic phase was combined with the previous organic phase, dried over magnesium sulfate, filtered with magnesium sulfate, and the solvent was distilled off from the obtained filtrate to obtain phenyl vinyl sulfone. 2.76 g (82.1% yield) was obtained.

Example 5 Instead of diisopropylethylamine, 230 mg (1.0 mmol) of triethylbenzylammonium chloride
By operating in the same manner as in Example 4 except that was used, 3.04 g (yield 90.4%) of phenylvinylsulfone was obtained.

Example 6 The procedure of Example 4 was repeated, except that 290 mg (2.0 mmol) of triisopropylamine was used instead of diisopropylethylamine, to obtain 3.33 g (yield 99.0%) of phenylvinyl sulfone. Obtained.

Example 7 The procedure of Example 4 was repeated, except that 300 mg (3.0 mmol) of diisopropylamine was used instead of diisopropylethylamine.
27 g (97.2% yield) were obtained.

Example 8 610 mg of 1,8-diazabicyclo [5.4.0] undec-7-ene instead of diisopropylethylamine
(4.0 mmol), and the procedure of Example 4 was repeated except that 3.04 g of phenylvinylsulfone (yield 9) was used.
0.4%).

Example 9 20.7 g of (β-chloroethylsulfonyl) benzene
(100 mmol) was dissolved in 60 g of toluene, and 0.53 g (5.2 mmol) of triethylamine was added.
The temperature was raised to ° C. To this solution was added 27.7 g of a 25% aqueous potassium carbonate solution (potassium carbonate 50.1 mmol) over 30 minutes.
After l) was added dropwise, the mixture was kept warm and stirred at 60 ° C for 3 hours. After cooling to room temperature, the organic phase was separated and 10 g of a 5% aqueous sulfuric acid solution was added.
And once with 10 g of water. The resulting toluene solution of phenylvinyl sulfone was partially concentrated to obtain a solution having a phenylvinyl sulfone concentration of 40%. 35 g of the solution
Was dropped into hexane at 20-30 ° C over 10 minutes, and then cooled to -10 ° C. The obtained crystals were separated by filtration, washed with 35 g of hexane, and then dried under reduced pressure.
16.2 g of phenylvinyl sulfone (96.3% yield)
I got

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300

Claims (17)

[Claims] 1. The general formula (1) (Wherein R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group,
Amino group, lower alkylamino group, di (lower alkyl)
X represents an amino group, and X represents a halogen atom. Wherein β-haloethylarylsulfone represented by formula (1) is reacted with an alkali metal salt in the presence of an amine. (In the formula, R ¹ and R ² each have the same meaning as described above.)
A method for producing an aryl vinyl sulfone represented by the formula: 2. The method for producing aryl vinyl sulfone according to claim 1, wherein the reaction is carried out in the presence of a hydrophobic organic solvent. 3. The process for producing aryl vinyl sulfone according to claim 1, wherein the alkali metal salt is an aqueous solution of an alkali metal salt. 4. The method for producing aryl vinyl sulfone according to claim 1, wherein the alkali metal salt is at least one selected from an alkali metal carbonate and an alkali metal bicarbonate. 5. The alkali metal carbonate is at least one selected from potassium carbonate and sodium carbonate.
5. The method for producing an aryl vinyl sulfone according to the above. 6. The method according to claim 4, wherein the alkali metal bicarbonate is at least one selected from potassium bicarbonate and sodium bicarbonate. 7. The arylvinylsulfone according to claim 1, wherein the amine is at least one selected from a secondary amine, a tertiary amine, an inorganic acid salt of a tertiary amine and a quaternary ammonium salt. Production method. 8. The method for producing aryl vinyl sulfone according to claim 7, wherein the secondary amine is dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine or diisobutylamine. 9. The tertiary amine is trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, diisopropylethylamine, N, N-dimethylbenzylamine, 1,5-diazabicyclo [4.3.0]. None-5
The method for producing an arylvinylsulfone according to claim 7, which is ene or 1,8-diazabicyclo [5.4.0] undec-7-ene. 10. The method according to claim 7, wherein the inorganic acid salt of a tertiary amine is trimethylamine hydrochloride or triethylamine hydrochloride. 11. The quaternary ammonium salt is triethylbenzylammonium chloride, triethylbenzylammonium bromide, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide,
The method for producing aryl vinyl sulfone according to claim 7, which is tetrabutylammonium chloride or tetrabutylammonium bromide. 12. The method for producing aryl vinyl sulfone according to claim 1, wherein the amount of the amine used is 0.005 to 0.5 mole times the β-haloethyl aryl sulfone. 13. The amount of the alkali metal salt used is 0.8% in terms of alkali metal relative to β-haloethylarylsulfone.
The method for producing an aryl vinyl sulfone according to any one of claims 1 to 3, which is at least molar times. 14. The method according to claim 1, wherein the reaction temperature is 0 to 150 ° C.
4. The method for producing an aryl vinyl sulfone according to any one of claims 1 to 3. 15. A process for producing aryl vinyl sulfone, wherein the solution containing aryl vinyl sulfone obtained in any one of claims 1 to 3 is crystallized to separate the aryl vinyl sulfone. 16. The method for producing aryl vinyl sulfone according to claim 15, wherein the crystallization treatment is a crystallization treatment in which a solution containing aryl vinyl sulfone and a solvent that does not substantially dissolve aryl vinyl sulfone are mixed. 17. The method for producing aryl vinyl sulfone according to claim 16, wherein the solvent that does not substantially dissolve aryl vinyl sulfone is an aliphatic hydrocarbon solvent.