JPH0611753B2 - Vitamin A manufacturing method - 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 product, 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 ¹ represents a halogen atom) and / or the general formula (2) (Wherein R ¹ is as defined above) in a hydrocarbon solvent in the general formula
(3) (In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents an alkyl group or an aralkyl group, and
Is a halogen atom, a lower alkoxy group, an acyloxy group,
It represents a hydrogen sulfate group or a hydroxyl group) and is treated with potassium hydroxide in the presence of a quaternary ammonium salt or crown ether.

R ¹ , X ¹ , R ² , R ³ , R ⁴ in the above general formula,
R ⁵ and X 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
Examples thereof include lower alkoxy groups such as -propoxy, n-propoxy, i-butoxy and n-butoxy. Further, the substituent may be located at any of the ortho position, the meta position and the para position, and may be one or a plurality of two or more. X represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom.

R ² , R ³ , R ⁴ and R ⁵ represent an alkyl group or an aralkyl group. Here, as the alkyl group, a linear or branched one having 1 to 20 carbon atoms is preferable, and a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n
-Butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, tridecyl group, octadecyl group, nonadecyl group and the like are exemplified. Examples of the aralkyl group include benzyl group, 1-phenylethyl group, 2-phenylethyl group and 3-phenylpropyl group. X is a halogen atom, a lower alkoxy group, an acyloxy group, hydrogen sulfate group (HSO ₄ -) or represents a hydrogen radical, a halogen atom chlorine, bromine, and iodine are exemplified, lower alkoxy as the methoxy group, an ethoxy group , Propoxy group, n-butoxy group, t-
Examples thereof include a butoxy group, and examples of the acyloxy group include a lower alkylcarbonyloxy group such as a formyloxy group, an acetoxy group and a propionyloxy group, and an arylcarbonyloxy group such as a benzoyloxy group.

Specific examples of the quaternary ammonium salt represented by the general formula (3) include tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide. , Hydrogen sulfate tetra-n
-Butylammonium, tetra-n-butylammonium methoxide, chlorinated benzyltrimethylammonium, chlorinated stearyltrimethylammonium and the like. The amount of the quaternary ammonium salt used is represented by the general formula (1)
The amount is 0.1 to 100 mol%, preferably 1 to 5 mol%, based on the halo sulfone represented by and the vinyl sulfone represented by the general formula (2).

The crown ether is a cyclic polyether having a total of four or more atoms capable of coordinating with a metal ion such as an oxygen atom, a nitrogen atom and a sulfur atom in the bonding portion forming the ring, for example, 12-crown-
4,15-crown-5,18-crown-6, dibenzo-18-crown-6, dicyclohexyl-18-crown-6 and the like can be mentioned. The amount of the crown ether used is 0.1 to the halo sulfone represented by the general formula (1) and / or the vinyl sulfone represented by the general formula (2).
The amount is 100 mol%, preferably 1 to 10 mol%.

The reaction for deriving the halosulfone represented by the general formula (1) and / or the vinylsulfone represented by the general formula (2) into vitamin A according to the present invention is desirably performed in a hydrocarbon solvent under an inert gas atmosphere. Examples of such a solvent include toluene, benzene, hexane, cyclohexane and the like. The amount of the solvent used is preferably an amount such that the concentration of halosulfone and / or vinylsulfone as the reaction raw material is about 0.05 to 2 mol /.

This reaction can be carried out within a temperature range of -10 ° C to 100 ° C, but a temperature range of 0-4 ° C is particularly preferable.

The amount of potassium hydroxide used in this reaction is preferably 1 to halosulfone and / or vinylsulfone.
The amount is 20 molar times, and more preferably 5 to 7 molar times. After completion of the reaction, a precipitate is filtered off from the reaction mixture, if necessary, and then water, saline solution or the like is 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. Etc. are used, and it is preferable to use these organic solvents in an amount such that the concentration of vitamin A is 0.1 to 5 mol /. As the tertiary amine, for example, triethylamine, pyridine, etc. are used.
These tertiary amines are about 1 to 10 relative to vitamin A.
It is preferable to use an equivalent amount, but by using an excessive amount, the tertiary amine can also serve as an organic solvent. When an alkali metal carbonate is used, 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 if necessary, and diluted sulfuric acid, water, saturated sodium hydrogen carbonate aqueous solution, sodium hydroxide aqueous 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 halosulfone and / or vinylsulfone 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 ² 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 ² are as defined above, X ¹ represents a halogen atom), and treated with a metal hydroxide such as sodium hydroxide or potassium hydroxide. The halosulfone represented by the general formula (1) and the vinyl sulfone 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-cyclohexen-1-yl) -9-phenylsulfonyl-2, was added to a nitrogen-substituted 200 ml flask. 7.29 g of 7-nonadiene (20 mmo
40 ml of toluene was added to l), and after stirring for a while, 5.89 g (10%) of powdery potassium hydroxide (95% purity) was obtained.
0 mmol) and tetraethylammonium chloride 66.3 mg
(0.4 mmol) was added and the mixture was stirred at 10 ° C. for 12 hours. 50 ml of 5% saline was added to the reaction solution 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 was separated, and this organic layer was further added with 100 ml of 5% saline.
It was washed twice with and the solvent was distilled off to obtain 12.8 g of a red oily substance. When this oily substance was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 80.9%, and the total trans isomer ratio in vitamin A acetate was 94.5%.

Example 2 1-Hydroxy-3, was added to a 200 ml flask purged with nitrogen.
7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-
40 ml of toluene was added to 8.56 g (20 mmol) of 2,6,8-nonatriene, and after stirring for a while, 5.89 g (100 mmol) of powdery potassium hydroxide (95% purity).
And 66.3 mg of tetraethylammonium chloride (0.4
mmol) was added and the mixture was stirred at 10 ° C. for 12 hours. 5% in the reaction solution
50 ml of saline was added and the layers were separated. Acetic anhydride 1 was added to this organic layer.
0 ml (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 10% sodium hydroxide aqueous 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. .6g
Got The yield of vitamin A acetate was 7 when this oil was quantified by high performance liquid chromatography.
It was 8.9%, and the total trans isomer ratio in vitamin A acetate was 94.3%.

Example 3 6-Chloro-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7- was added to a nitrogen-substituted 200 ml flask. 2.6 g (5.6 mmol) of nonadiene and 1-hydroxy-3,7-dimethyl-9- (2,6,6)
-Trimethyl-1-cyclohexen-1-yl) -9-
Phenylsulfonyl-2,6,8-nonatoluene 6.1
To a mixture of 6 g (14.4 mmol), 40 ml of toluene was added, and after stirring for a while, powdery potassium hydroxide (9
5% purity) 5.89 g (100 mmol) and tetraethylammonium chloride 66.3 mg (0.4 mmol) were added and 1
Stirred at 0 ° C. for 12 hours. 50 ml of 5% saline was added to the reaction solution to separate it. 10 ml of acetic anhydride (105.
4 mmol) and 0.9 g of sodium carbonate were added, and the mixture was stirred at 40 ° C. for 3 hours. 10% aqueous sodium hydroxide solution 10
After adding 0 ml to the reaction solution, the organic layer was separated, and this organic layer was washed twice with 100 ml of 5% saline solution, and the solvent was distilled off to obtain 12.3 g of a red oily substance. When this oily substance was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 77.9%,
The total trans isomer ratio in vitamin A acetate is 9
It was 4.5%.

Example 4 6-Chloro-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7- was placed in a nitrogen-substituted 200 ml flask. 2.6 g (5.6 mmol) of nonadiene and 1-hydroxy-3,7-dimethyl-9- (2,6,6)
-Trimethyl-1-cyclohexen-1-yl) -9-
Phenylsulfonyl-2,6,8-nonatriene 6.1
After adding 40 ml of toluene to a mixture of 6 g (14.4 mmol) and stirring for a while, powdery potassium hydroxide (95
% Purity) 5.89 g (100 mmol) and 12-crown-
471 mg (0.4 mmol) was added and it stirred at 10 degreeC for 12 hours. 50 ml of 5% saline was added to the reaction solution 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. 1
After adding 100 ml of 0% 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. 13.1 g was obtained. When this oil was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 78.2%, and the total trans isomer ratio in vitamin A acetate was 93.8%.

〔The invention's effect〕

According to the method of the present invention, as is clear from the above examples, vitamin A and its acetate can be easily produced in good yield and easily from industrial raw materials that are easily available at low cost.

Claims (1)

[Claims] 1. A general formula (1) (Wherein R ¹ represents an optionally substituted phenyl group and X ¹ represents a halogen atom) and / or the general formula (2) (Wherein R ¹ is as defined above) in a hydrocarbon solvent in the general formula
(3) (In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents an alkyl group or an aralkyl group, and
Is a halogen atom, a lower alkoxy group, an acyloxy group,
(Representing a hydrogen sulfate group or a hydroxyl group) is treated with potassium hydroxide in the presence of a quaternary ammonium salt represented by or a crown ether.