JPH068279B2 - Method for producing hydroxysulfones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention provides compounds represented by general formula (I) (In the formula, R ¹ represents an optionally substituted phenyl group.) The hydroxy vinyl sulfone represented by: or the hydroxy vinyl sulfone and the general formula (II) (Wherein R ¹ represents an optionally substituted phenyl group and X represents a halogen atom), and a method for producing a mixture with a hydroxyhalosulfone.

It is known that these hydroxysulfones are useful as synthetic intermediates for vitamin A or its carboxylic acid ester, which are used as additives for medicines and feeds (see Patent Publication below).

JP-A-62-87559, JP-A-62-87561, JP-A-62-89652, JP-A-62-89657 [Prior Art] In the above patent publications, among these hydroxysulfones, The hydroxyhalosulfone represented by the formula (II) has the general formula (III) (Wherein R ¹ represents an optionally substituted phenyl group, R ² represents a lower acyl group, and X represents a halogen atom), and an acyloxyhalosulfone represented by the general formula
The hydroxyvinyl sulfone represented by (I) has the general formula (IV) (In the formula, R ¹ represents an optionally substituted phenyl group, and R ² represents a lower acyl group.) Each can be produced by treating an acyloxyvinyl sulfone with an alkali metal hydroxide. Is stated. Further, as the reaction conditions at that time, it is preferable to use "alcohols such as methanol and ethanol as a solvent, or a mixture of these alcohols and water and / or hydrocarbons such as benzene and toluene, ) When a mixture of alcohols and water and / or hydrocarbons is used as a solvent, it is desirable to use the water and / or hydrocarbons to such an extent that the reaction system does not cause phase separation. ” Has been done.

[Problems to be Solved by the Invention]

General formula (II) or general formula described in the above patent publication
According to the method for producing a hydroxysulfone represented by (I), methanol as a solvent to homogenize the reaction system,
It is essential to use alcohols such as ethanol in fairly large amounts. However, in this case, in order to separate the target hydroxysulfones and the by-product alkali metal salt of carboxylic acid and the remaining alkali metal hydroxide after completion of the reaction, a larger amount of It is necessary to add water and hydrocarbons for liquid separation.

As described above, the general formula (I) described in the above patent publication
Alternatively, the method for producing a hydroxysulfone represented by the general formula (II) is excellent in itself, but requires a large amount of an organic solvent and water, which means that the larger the production scale, the more operational and costly. It is an issue that needs to be solved as the above problem.

[Means for Solving the Problems]

As a result of intensive studies to solve the above-mentioned problems, the present inventors have shown that in the presence of a lower alcohol, a target reaction rapidly proceeds even in a heterogeneous system such as liquid-liquid or solid-liquid, and the general formula ( III) acyloxy halo sulfone or a mixture of the sulfone and the acyloxy vinyl sulfone represented by the general formula (IV) directly from the hydroxy vinyl sulfone represented by the general formula (I) or the sulfone and the general formula (II) It was found that a mixture with a hydroxyhalosulfone represented by the formula (1) can be obtained in a high yield, and that the production method can reduce the amounts of the organic solvent and water used, and the operation is simple.

Here, the "heterogeneous system" means a reaction system in which a state where two or more kinds of phases are separated can be visually recognized. For example, a liquid-liquid heterogeneous system is formed by an organic solvent layer and an aqueous layer which are separated from each other. Further, the solid-liquid heterogeneous system is formed by the organic solvent layer and the solid substance which is not dissolved therein. Further, in some cases, a solid-liquid-liquid heterogeneous system in which they are combined is present.

It is generally known that the reaction rate in a heterogeneous system is lower than that in a homogeneous system. For example, when synthesizing a corresponding alcohol by hydrolysis of carboxylate ester with hydroxide ion, it is common to carry out the reaction in a homogeneous system using methanol, ethanol, etc. as a solvent, and when using a heterogeneous system. It was necessary to add a quaternary ammonium salt as a phase transfer catalyst in order to accelerate the reaction (see J. Am. Chem. Soc., 93, 195 (1971)). On the other hand, the present inventors have found that the effect of adding a lower alcohol is far greater than that of a quaternary ammonium salt in a hydrolysis reaction in a heterogeneous system, and have completed the present invention. .

That is, according to the present invention, the above-mentioned object is represented by the general formula (III) (In the formula, R ¹ represents an optionally substituted phenyl group, R ² represents a lower acyl group, and X represents a halogen atom.) An acyloxyhalosulfone represented by the formula: (Wherein R ¹ represents an optionally substituted phenyl group and R ² represents a lower acyl group), and a mixture with an acyloxyvinyl sulfone represented by the following formula:
General formula (I) characterized by treatment with an alkali metal hydroxide in a liquid-liquid or solid-liquid heterogeneous system in the presence of a lower alcohol (In the formula, R ¹ represents an optionally substituted phenyl group.) The hydroxy vinyl sulfone represented by: or the hydroxy vinyl sulfone and the general formula (II) (Wherein R ¹ represents an optionally substituted phenyl group, and X represents a halogen atom) and a method for producing a mixture with a hydroxyhalosulfone.

R ¹ , R ² and X in the above general formula will be described in detail.

R ¹ represents an optionally substituted phenyl group, wherein the substituent is a lower alkyl group such as methyl, ethyl, i-propyl, n-propyl, i-butyl, n-butyl; chlorine, bromine, iodine. Halogen atoms such as; and methoxy, ethoxy, i-propoxy, n-propoxy,
Lower alkoxy groups such as i-butoxy and n-butoxy are exemplified. Further, the substituent may be at any position of the ortho position, the meta position or the para position, and may be one or a plurality of two or more. R ² represents a lower acyl group such as formyl, acetyl and propionyl. Also, X
Represents a halogen atom such as chlorine, bromine or iodine.

Next, the content of the present invention will be described in detail.

As the alkali metal hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used, but sodium hydroxide is preferable in terms of price. Although the alkali metal hydroxide can be used as a solid or an aqueous solution, it is convenient to use a commercially available product as it is. Therefore, use a solid sodium hydroxide or an about 50% aqueous solution. Is preferred. The amount of alkali metal hydroxide used is determined by the general formula (I
About 1 to about 1 mol of the total amount of the acyloxyhalosulfone represented by II) or the acyloxyhalosulfone represented by the general formula (IV).
An amount of 10 mol is preferred.

This reaction is preferably carried out in a state where the acyloxyhalosulfone represented by the general formula (III) or the acyloxyhalosulfone and the acyloxyvinylsulfone represented by the general formula (IV) are dissolved in an organic solvent. Suitable solvents include hydrocarbons such as cyclohexane and toluene. The amount of the solvent used is such that the concentration of the acyloxyhalosulfone represented by the general formula (III) or the total amount of the acyloxyhalosulfone and the acyloxyvinylsulfone represented by the general formula (IV) is about 0.1 to 10 mol / 1. It is preferable that the amount is

The lower alcohol added to the reaction system is methanol,
Examples thereof include ethanol, n-propyl alcohol, i-propyl alcohol, n-butyl alcohol, n-amyl alcohol, and the like, with methanol being particularly preferable.
The lower alcohol is used in an amount of about 0.1 to 20 mol per mol of the acyloxyhalosulfone represented by the general formula (III) or the total amount of the acyloxyhalosulfone and the acyloxyvinylsulfone represented by the general formula (IV). The amount is appropriate.

This reaction can be carried out in the range of about 0 to 60 ° C, preferably about 10 to 40 ° C.

A suitable reaction method is to dissolve the acyloxyhalosulfone represented by the general formula (III) or the acyloxyhalosulfone represented by the general formula (IV) and the acyloxyvinylsulfone represented by the general formula (IV) in the above organic solvent, and add the above lower alcohol thereto. After the addition, a method of adding an alkali metal hydroxide (solid or aqueous solution) to this solution, mixing the alkali metal hydroxide (solid or aqueous solution) with the above lower alcohol, and adding the compound of the general formula ( There may be mentioned two methods of adding the acyloxyhalosulfone represented by III) or a solution of the acyloxyhalosulfone represented by the general formula (IV) and the acyloxyvinylsulfone represented by the general formula (IV) in the organic solvent. In any case, the system is heterogeneous when the reaction is occurring.

The hydroxyvinyl sulfone represented by the general formula (I) or the mixture of the sulfone and the hydroxyhalosulfone represented by the general formula (II) obtained by this reaction can be easily separated as follows.

First, by adding water and an organic solvent such as cyclohexane or toluene to the reaction mixture (heterogeneous system) and separating the mixture, the target hydroxysulfones are taken into the organic solvent, and water-soluble salts or by-products that remain as by-products remain. Separates from hydroxides of alkali metals. This separation operation can also be performed by filtration, and the target hydroxysulfone can be obtained in the same manner as a solution of an organic solvent. Then, this solution is washed with water or the like, if necessary, and then the solvent is distilled off to give the hydroxyvinyl sulfone represented by the general formula (I) or the sulfone and the hydroxyhalosulfone represented by the general formula (II). A crude product of a mixture with can be obtained. From this crude product, the general formula (I)
Or a general formula (II)
Although the hydroxyhalosulfone represented by can be isolated by column chromatography or the like, the crude product can be used as it is for the production of vitamin A or its carboxylic acid ester.

The acyloxyhalosulfone represented by the general formula (III), which is a starting material compound of the method of the present invention, is the same as the acyloxy halosulfone represented by the general formula (IV) according to the method described in JP-A-62-87559. Vinyl sulfone can be produced by the method described in JP-A-62-89652. However, as shown in Reference Examples, it is known that these acyloxysulfones are usually obtained as a mixture, and both of them are raw materials for vitamin A or its carboxylic acid ester. There is no problem even if you continue to use it.

〔Example〕

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Example 1 1-Acetoxy-6- for test tubes with screw caps
Chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene 1.1295 g (2.23 mmol), toluene 3 m and methanol 0.4160 g (13.0 mmol) was added, and then 50% aqueous sodium hydroxide solution was added to this solution.
0.9118 g (11.4 mmol) was added. Immediately a precipitate is deposited,
The reaction system became heterogeneous. The test tube was placed in a water bath at 20 ° C., the contents were stirred for 1 hour, and then 30 m of toluene and 10 m of water were added to the reaction mixture. The precipitate dissolved and the system separated into two layers. These were transferred to a separating funnel, and 50 m of toluene and 10 m of water were further added for liquid separation. The toluene layer was transferred to an eggplant-shaped flask, and toluene was removed under reduced pressure to obtain 1.6387 g of a yellow oil.

Analysis of this oil by high performance liquid chromatography revealed that 1-hydroxy-3,7-dimethyl-9- (2,6,6
-Trimethyl-1-cyclohexen-1-yl) -9-
Phenylsulfonyl-2,6,8-nonatriene (IA) 0.
8085 g (1.89 mmol) and 6-chloro-1-hydroxy-
3,7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-
It was found that 0.1428 g (0.31 mmol) of 2,7-nonadiene (II-A) was contained. Therefore, the total yield is 98.
It was 5%.

Examples 2 to 4 The reaction and treatment operations were performed in the same manner as in Example 1 except that the amounts of methanol and sodium hydroxide aqueous solution used were changed to the amounts shown in Table 1, and hydroxysulfones (I
-A) or a mixture of (IA) and (II-A) was obtained. The results are summarized in Table 1.

Examples 5 to 6 In Example 1, the amounts of methanol and aqueous sodium hydroxide used were changed to the amounts shown in Table 2, and the reaction was carried out at 35%.
A reaction and a treatment operation were carried out in the same manner except that the reaction was carried out in a water bath at ℃ for 2 hours to obtain a mixture of hydroxysulfones (IA) and (II-A). The results are summarized in Table 2.

Examples 7 to 9 In the same manner as in Example 1, except that the lower alcohol shown in Table 3 was used in place of methanol, the reaction and treatment operations were performed, and the hydroxysulfones (IA) and (II-A) were obtained.
To obtain a mixture with. The results are summarized in Table 3.

Examples 10 to 12 In the same manner as in Example 1, except that the solid or aqueous solution of the alkali metal hydroxide shown in Table 4 was used in place of the 50% sodium hydroxide aqueous solution, the reaction and treatment operations were performed in the same manner, and hydroxysulfones were obtained. (IA) or (IA)
And a mixture of (II-A) was obtained. The results are summarized in Table 4.

Example 10 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-
Cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene 72.50 g (0.143 mol) and 1-acetoxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene-1) -Yl) -9-phenylsulfonyl-2,6,8-nonatriene 210.00 g of a toluene solution containing 6.24 g (0.013 mol) was added, and toluene 15 m was added thereto.
After adding 19 m (0.47 mol) of methanol and 37.85 g (0.47 mol) of 50% aqueous sodium hydroxide solution was added dropwise over 10 minutes while maintaining the internal temperature at 20 to 25 ° C. A precipitate was formed with the dropping, and the system became heterogeneous.

After continuing stirring at 22 to 24 ° C for 2 hours, water was added to the reaction mixture.
The precipitate was dissolved by adding 150 m. Transfer the contents of the flask to a separatory funnel, and add 50 m of water and 2 toluene.
50 m was added and the layers were separated.

After separating the toluene layer, the aqueous layer was extracted with 150 m of toluene. The toluene layers were combined and washed with 300 m of a 2% sodium carbonate aqueous solution. The toluene layer was transferred to an eggplant-shaped flask, and toluene was distilled off under reduced pressure to obtain 120.02 g of red oil.

Analysis of this oil by high performance liquid chromatography revealed that 1-hydroxy-3,7-dimethyl-9- (2,6,6
-Trimethyl-1-cyclohexen-1-yl) -9-
Phenylsulfonyl-2,6,8-nonatriene (IA) 4
9.75 g (0.116 mol) and 6-chloro-1-hydroxy-
3,7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-
It was found that 16.12 g (0.035 mmol) of 2,7-nonadiene (II-A) was contained. Therefore, the total yield is 96.
It was 6%.

Reference example 1 In a 500 m three-necked flask, 1-acetoxy-8-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-
1-Cyclohexen-1-yl) -9-phenylsulfonyl-2,6-nonadiene in toluene solution containing 147.3 g (0.302 mol) 377.69 g, toluene 20 m and N, N
-Dimethylformamide (67.50 g) was added, and a solution of thionyl chloride (34.0 m, 0.467 mol) in toluene (30 m) was added dropwise thereto while keeping the internal temperature at 10 ° C or lower.

After completion of dropping, stirring was continued for 20 minutes, and 400 g of 13% aqueous sodium hydroxide solution was gradually added to the reaction mixture. The contents of the flask were transferred to a separating funnel, and 200 m of toluene was added to separate the layers.

The toluene layer was separated, and the aqueous layer was extracted with 100 m of toluene. Combine the toluene layers with a 2% aqueous sodium carbonate solution.
After washing with 300 m, toluene was distilled off under reduced pressure to obtain 277.94 g of reddish brown oil.

Analysis of this oil by high performance liquid chromatography revealed that 1-acetoxy-6-chloro-3,7-dimethyl-
9- (2,6,6-trimethyl-1-cyclohexene-1-
Yl) -9-phenylsulfonyl-2,7-nonadiene
140.1 g (0.277 mol) and 1-acetoxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,6,8-nonatriene 12.09 It was found that g (0.026 mol) was contained. Therefore, the total yield was quantitative. .

〔The invention's effect〕

According to the method of the present invention, a hydroxyvinyl sulfone represented by the general formula (I) or a mixture of the sulfone and a hydroxyhalosulfone represented by the general formula (II) can be easily operated as apparent from the above-mentioned examples. Can be produced in high yield, and as a result, hydroxysulfones useful as synthetic intermediates for these vitamin A or its carboxylic acid ester can be obtained at low cost.

Claims (1)

[Claims] 1. General formula (III) (In the formula, R ¹ represents an optionally substituted phenyl group, R ² represents a lower acyl group, and X represents a halogen atom.) An acyloxyhalosulfone represented by the formula: (Wherein R ¹ represents an optionally substituted phenyl group and R ² represents a lower acyl group), and a mixture with an acyloxyvinyl sulfone represented by the following formula:
General formula (I) characterized by treatment with an alkali metal hydroxide in a liquid-liquid or solid-liquid heterogeneous system in the presence of a lower alcohol (In the formula, R ¹ represents an optionally substituted phenyl group.) The hydroxy vinyl sulfone represented by: or the hydroxy vinyl sulfone and the general formula (II) (In the formula, R ¹ represents an optionally substituted phenyl group, and X represents a halogen atom.) A method for producing a mixture with a hydroxyhalosulfone.