JPH0611752B2 - 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 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) (In the formula, R ¹ represents an optionally substituted phenyl group, R ² represents a lower acyl group, X ¹ represents a halogen atom), and a halosulfone represented by General formula (2) (Wherein R ³ , R ⁴ , R ⁵ , and R ⁶ are the same or different and each represents an alkyl group or an aralkyl group, and X represents a halogen atom, a lower alkoxy group, an acyloxy group, a hydrogensulfate group, or a hydroxyl group). Quaternary ammonium salt and general formula (3) (In the formula, R ⁷ , R ⁸ and R ⁹ are the same or different and each is a hydrogen atom, and substituted with a group represented by —CH ₂ (OCH ₂ CH ₂ ) nOCH ₃ (n is 0 or an integer of 1 or 2). (Representing an alkyl group, an aryl group or an aralkyl group which may be optionally present) is treated with potassium hydroxide in the presence of an alcohol represented by

R ¹ , R ² , X ¹ , R in the above general formulas (1) and (2)
³ , R ⁴ , R ⁵ , R ⁶ 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 or n-butyl;
Halogen atom such as chlorine, bromine, iodine; and methoxy, ethoxy, i-propoxy, n-propoxy, i-
Examples thereof include lower alkoxy groups such as 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. R ² represents a lower acyl group such as formyl, acetyl and propionyl. X ¹ represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom.

R ³ , R ⁴ , R ⁵ and R ⁶ 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 (2) include chlorinated tetraethylammonium, brominated tetraethylammonium, iodinated tetraethylammonium, chlorinated tetra-n-butylammonium and brominated tetra-n-butylammonium. , 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)
0.1 to 100 mol based on the halosulfone
%, Preferably 1-5 mol%.

This reaction should desirably be carried out in a hydrocarbon solvent or ether solvent under an inert gas atmosphere, and as the hydrocarbon solvent, toluene, benzene, hexane,
Cyclohexane and the like, and examples of the ether solvent include tetrahydrofuran, diethyl ether, isopropyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether and the like. Of these, the use of tetrahydrofuran is particularly preferable. The solvent generally has a concentration of halosulfone as a reaction raw material of about 0.05 to 2 mol.
However, the numerical range is not necessarily limited.

R ⁷ , R ⁸ and R ⁹ in the general formula (3) are hydrogen atoms,
_{-CH 2 (OCH 2 CH 2)} nOCH 3 (n is 0 or 1 or 2 of the integer is) represented by the alkyl group which may be substituted with a group, an aryl group or an aralkyl group. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, etc.
Those of -6 are preferred. -CH ₂ (OCH ₂ CH ₂ ) nOCH ₃ (n is 0
Or an integer of 1 or 2) is substituted with a group represented by methoxymethyl group, 2
A methoxyethoxymethyl group and a 2- (2-methoxyethoxy) ethoxymethyl group. Examples of the aryl group include a phenyl group, a tolyl group, a xylyl group and the like. Examples of the aralkyl group include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group and a 3-phenylpropyl group.

Specific examples of alcohols represented by the general formula (3) include methanol, ethanol, i-propanol, t-butanol, benzyl alcohol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, and the like. Among the general formula (4) (In the formula, n represents an integer of 1, 2, or 3) It is preferable to use ethylene glycol monomethyl ethers. The amount of these alcohols to be used is preferably 0.01 mol to 30 mol, and more preferably 0.1 mol to the halosulfone represented by the general formula (1).
The amount is 5 to 2 mol.

The amount of potassium hydroxide used in this reaction is determined by the general formula
The amount is 1 to 20 times, and more preferably 3 to 7 times the amount of the halosulfone represented by (1).

This reaction can be carried out within a temperature range of 0 to 120 ° C, but a temperature range of 0 to 40 ° C is particularly preferable. 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. Examples of the acylating agent include acetic anhydride, acetyl chloride,
Palmitoyl chloride or the like is 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 for vitamin A.
It is preferable to use 10 to 10 equivalents, but the tertiary amine can also serve as an organic solvent by using an excessive amount. 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 represented by the general formula (1), which is 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 ² is as defined above) in the presence of an anionizing agent such as Grignard reagent or alkyl lithium (Wherein R ¹ and R ² are as defined above), and a halogenating agent such as thionyl chloride is allowed to act on the hydroxysulfone.

〔Example〕

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

Example 1. Example using tetrahydrofuran solvent 1-acetoxy-6-in a 300 ml flask purged with nitrogen.
Chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene 22.32 g (44 mm
ol) and THF (75 ml) and stirred for a while, then 370 mg (1.76 mm) of tetraethylene ammonium chloride
ol), 3.34 g of 2-methoxyethanol (44 mmo
l), potassium hydroxide (purity 95%) 13 g (220 mmol)
Was added and stirred at 30 ° C. for 6.5 hours. To the reaction solution were added 100 ml of toluene and 50 ml of 5% saline, and the layers were separated. 20.2 ml (213 mmol) of acetic anhydride and 1.87 g of sodium carbonate were added to this organic layer, and the mixture was stirred at 40 ° C. for 3 hours. 1
200 ml of 0% sodium hydroxide aqueous solution was added to the reaction solution, the organic layer was separated, and the organic layer was further added with 5% saline solution 1
It was washed twice with 00 ml and the solvent was distilled off to obtain 22 g of a red oily substance.

When this oily substance was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6).
6-trimethyl-1-cyclohexen-1-yl) -9
It was 82.4% based on -phenylsulfonyl-2,7-nonadiene, and the total trans isomer ratio in vitamin A acetate was 94.6%.

Example 2. Example using a toluene solution 1-acetoxy-6-
Chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene 22.32 g (44 mmo
l) and 100 ml of toluene and after stirring for a while, 567 mg of tetra-n-butylammonium bromide
(1.76 mmol) Methanol 1.41 g (44 mmol),
13 g (220 mmol) of potassium hydroxide (purity 95%) was added, and the mixture was stirred at 40 ° C. for 11 hours. 5% saline 5 in the reaction solution
0 ml was added and the layers were separated. 20.2 ml of acetic anhydride was added to this organic layer.
(213 mmol) and 1.87 g of sodium carbonate were added and 4
Stirred at 0 ° C. for 3 hours. After adding 200 ml of a 10% aqueous sodium hydroxide solution to the reaction solution, the organic layer was separated, and this organic layer was washed twice with 100 ml of 50% brine, and the solvent was distilled off to give a red oily product. 01 g was obtained. When this oil was quantified by high performance liquid chromatography, the yield of vitamin A acetate was 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,2.
6,6-Trimethyl-1-cyclohexen-1-yl)
It was 79.8% based on -9-phenylsulfonyl-2,7-nonadiene, and the total trans isomer ratio in vitamin A acetate was 92.0%.

〔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 (3)

[Claims] 1. A general formula (1) (In the formula, R ¹ represents an optionally substituted phenyl group, R ² represents a lower acyl group, X ¹ represents a halogen atom), and a halosulfone represented by General formula (2) (Wherein R ³ , R ⁴ , R ⁵ , and R ⁶ are the same or different and each represents an alkyl group or an aralkyl group, and X represents a halogen atom, a lower alkoxy group, an acyloxy group, a hydrogensulfate group, or a hydroxyl group). Quaternary ammonium salt and general formula (3) (In the formula, R ⁷ , R ⁸ and R ⁹ are the same or different and each is a hydrogen atom, and substituted with a group represented by —CH ₂ (OCH ₂ CH ₂ ) nOCH ₃ (n is 0 or an integer of 1 or 2). (Representing an alkyl group, an aryl group or an aralkyl group which may be added) is treated with potassium hydroxide in the presence of an alcohol represented by the formula (4). 2. An alcohol represented by the general formula (3) is represented by the general formula
(Four) The method according to claim 1, which is ethylene glycol monomethyl ether represented by the formula (n represents an integer of 1, 2, or 3). 3. The method according to claim 1, wherein the ethereal solvent is tetrahydrofuran.