JPH0611751B2 - Method for producing vitamin A - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing vitamin A. Vitamin A and its carboxylic acid ester represented by acetate and palmitate are used in large amounts as medicines, feed additives and the like.

[Conventional technology]

Conventionally, as a method for producing vitamin A, JP-A-62-87561
As described in Japanese Patent Laid-Open Publication No. 2004-242242, there is known a method for producing vitamin A by treating halosulfone with a base in a hydrocarbon solvent.

[Problems to be Solved by the Invention] According to the above conventional method, vitamin A can be obtained in a relatively good yield when halosulfone which is a reaction raw material is treated with potassium alkoxide. There are problems in terms of availability and price, and this method is not always satisfactory in reaction results, and there is still room for improvement.

Therefore, an object of the present invention is to provide a method for producing vitamin A with good results by using an industrially general-purpose and inexpensive base.

[Means for Solving the Problems]

According to the present invention, the above-mentioned object is represented by the general formula (1) (Wherein R ¹ represents an optionally substituted phenyl group, and X represents a halogen atom) and / or the general formula (2) (Wherein R ¹ is as defined above) and is achieved by treating the vinyl sulfone with potassium hydroxide in an ether solvent.

R ¹ and X ¹ in the above general formula will be described in detail. R ¹ represents an optionally substituted phenyl group,
Here, as the substituent, methyl, ethyl, i-propyl,
Lower alkyl groups such as n-propyl, i-butyl and n-butyl; halogen atoms such as chlorine, bromine and iodine; and lower such as methoxy, ethoxy, i-propoxy, n-propoxy, i-butoxy and n-butoxy. An alkoxy group is 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. X is a chlorine atom, a bromine atom,
Represents a halogen atom such as an iodine atom.

The reaction for introducing the halosulfone represented by the general formula (1) and / or the vinyl sulfone represented by the general formula (2) into vitamin A according to the present invention is desirably performed in an ether solvent under an inert gas atmosphere. And examples of such solvents include tetrahydrofuran, diisopropyl ether, diethyl ether, t-butyl methyl ether,
Examples thereof include ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and tetraethylene glycol dimethyl ether. Of these, the use of tetrahydrofuran is particularly preferable. The solvent is generally used in such an amount that the concentration of halosulfone and / or vinylsulfone, which is a reaction raw material, becomes about 0.05 to 2 mol /, but this numerical range is not necessarily limited. The amount of potassium hydroxide used in this reaction is preferably 1 to 20 relative to halosulfone and / or vinylsulfone.
It is a mol amount, and more preferably 3 to 7 mol amount.

This reaction can be carried out within a temperature range of -10 ° C to 100 ° C, but a temperature range of 0-40 ° C is particularly preferable. After completion of the reaction, a precipitate is filtered off from the reaction mixture as needed, and then water, saline solution and the like are added to the reaction mixture to separate the organic layer. Vitamin A can be obtained by subjecting the obtained organic layer to purification means such as recrystallization and column chromatography.

Vitamin A thus obtained can be converted into a carboxylic acid ester of vitamin A by acylation by a conventional method. Examples of the carboxylic acid ester of vitamin A include vitamin A acetate and vitamin A palmitate. This acylation reaction is preferably performed in an organic solvent containing an organic layer containing vitamin A separated from the reaction mixture obtained by the above-described reaction for producing vitamin A or a vitamin A separated and purified from the organic layer, preferably in a third organic solvent. It is carried out by reacting an acylating agent in the presence of a primary amine or an alkali metal carbonate. As the acylating agent, for example, acetic anhydride, acetyl chloride, palmitoyl chloride and the like are used. The amount of the acylating agent used is preferably about 1 to 10 equivalents with respect to vitamin A. Examples of the organic solvent include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; ethers such as diethyl ether and diisopropyl ether; esters such as ethyl acetate and butyl acetate. It is preferable that these organic solvents are used in an amount such that the concentration of vitamin A is about 0.1 to 5 mol /. As a tertiary amine,
For example, triethylamine, pyridine, etc. are used. These tertiary amines are approximately 1 to 1 with respect to vitamin A.
It is preferable to use 10 equivalents, but the tertiary amine may also serve as an organic solvent by using an excessive amount. For salting with an alkali metal carbonate, for example, sodium carbonate, potassium carbonate, lithium carbonate, etc. are used, and the amount used is preferably 0.1 to 5 equivalents relative to the acylating agent.

The reaction is preferably carried out in the temperature range of about -10 ° C to 50 ° C. After completion of the reaction, a precipitate is filtered off from the reaction mixture as needed, and diluted sulfuric acid, water, saturated aqueous sodium hydrogen carbonate solution, aqueous sodium hydroxide solution and the like are added to the reaction mixture to separate the organic layer. Recrystallize the obtained organic layer,
The carboxylic acid ester of vitamin A can be obtained by subjecting to purification means such as column chromatography.

The halosulone and / or vinyl sulfone used as a raw material in the present invention is produced according to the method described in JP-A-62-87559. That is, the general formula (5) (Wherein R ¹ is as defined above) and a compound of the general formula (6) (Wherein R ⁶ represents a lower acyl group), and the compound represented by the general formula (7) is prepared by reacting with a compound represented by the formula (7) in the presence of an anionizing agent such as Grignard reagent and alkyllithium. (Wherein R ¹ and R ⁶ are as defined above), a halogenating agent such as thionyl chloride is allowed to act on the hydroxysulfone represented by the general formula (8) (Wherein R ¹ and R ⁶ are as defined above, and X represents a halogen atom), and the compound is generally treated with a metal hydroxide such as sodium hydroxide or potassium hydroxide. The halosulfone represented by the formula (1) and the vinylsulfone represented by the general formula (2) can be selectively produced, or they can be produced as a mixture. According to the present invention, these halosulfones and vinylsulfones can lead to vitamin A in good yields, respectively, and these compounds can lead to vitamin A in yields that may be used as a mixture. .

〔Example〕

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

Example 1 6-chloro-1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1 was added to a 200 ml flask purged with nitrogen.
-Microhexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene 9.29 g (20 mmol) of tetrahydrofuran 40 ml was added, and after stirring for a while, powdery potassium hydroxide (95% purity) 5.89 g ( 100
mmol) was added and the mixture was stirred at 10 ° C. for 8.5 hours. 100 ml of toluene and 50 ml of 5% saline were added to the reaction liquid to separate it. To this organic layer were added 10 ml (105.4 mmol) of acetic anhydride and 0.9 g of sodium carbonate, and the mixture was stirred at 40 ° C for 3 hours. After adding 100 ml of 10% sodium hydroxide aqueous solution to the reaction solution, the organic layer is separated, and the organic layer is further separated into 5
The extract was washed twice with 100 ml of a saline solution, and the solvent was distilled off to obtain 13.96 g of a red oily substance. When this oil was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 81.2%, and the total trans ratio in vitamin A acetate was 94.0%.
Met.

Example 2 1-Hydroxy-3,7 was added to a nitrogen-substituted 200 ml flask.
-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,6,8
-Nonatriene (8.56 g, 20 mmol) in 40 ml of tetrahydrofuran was added, and after stirring for a while, 5.89 g (100 mmol) of powdery potassium hydroxide (95% purity).
Was added and the mixture was stirred at 10 ° C. for 8.5 hours. 100 ml of toluene and 50 ml of 5% saline were added to the reaction liquid to separate it. To this organic layer, 10 ml (105.4 mmol) of acetic anhydride and 0.9 g of sodium carbonate were added, and the mixture was stirred at 40 ° C for 3 hours. 10%
After adding 100 ml of aqueous sodium hydroxide solution to the reaction solution, the organic layer is separated, and the organic layer is further added with 5% saline solution 1
It was washed twice with 00 ml and the solvent was distilled off to obtain 14.10 g of a red oily substance. When this oily substance was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 80.5%, and the total trans isomer ratio in the vitamin A acetate was 94.3%.

Example 3 6-chloro-1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1 was added to a nitrogen-substituted 200 ml flask.
-Cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadicon 2.6 g (5.6 mmol) and 1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-
1-Cyclohexen-1-yl) -9-phenylsulfonyl-2,6,8-nonatriene 6.16 g (14.4 mmo)
40 ml of tetrahydrofuran was added to the mixture of l), and after stirring for a while, 5.89 g (100 mmol) of powdery potassium hydroxide (95% purity) was added and 8.5 at 10 ° C.
Stir for hours. 100 ml of toluene and 50 ml of 5% saline were added to the reaction liquid to separate it. 10 ml of acetic anhydride in this organic layer
(105.4 mmol) and 0.9 g of sodium carbonate were added, and the mixture was stirred at 40 ° C. for 3 hours. After adding 100 ml of a 10% aqueous sodium hydroxide solution to the reaction solution, the organic layer was separated, and the organic layer was washed twice with 100 ml of 5% saline solution, and the solvent was distilled off to give a red oily substance 13 0.75 g was obtained. When this oily substance was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 80.4.
%, And the total trans isomer ratio in vitamin A acetate was 94.2%.

〔The invention's effect〕

According to the method of the present invention, as is clear from the above examples, it is possible to easily produce vitamin A and further its acetate from industrial raw materials which can be easily obtained at low cost.

Claims (1)

[Claims] 1. A general formula (1) (Wherein R ¹ represents an optionally substituted phenyl group, and X represents a halogen atom) and / or the general formula (2) (In the formula, R ¹ is as defined above) A method for producing vitamin A, comprising treating vinyl sulfone represented by the formula with potassium hydroxide in an ether solvent.