JPH0217172A - Production of vitamin a or caboxylic acid ester thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing vitamin A or its carboxylic acid ester. vita i/a and its ace f-),
Carboxylic acid esters represented by #A/i tate are used in large quantities as medicines, feed additives, and the like.

[Conventional technology]

Conventionally, as a method for manufacturing vitamins, Japanese Patent Application Laid-open No. 62-8
As described in Japanese Patent No. 7561, a method for producing vitamin A by treating halosulfo/ with a base in a hydrocarbon solvent is known.

When the halosulfone is treated with potassium alkoxide, vitamin A can be obtained in relatively good yield, but
Potassium alkoxide is easy to obtain, but there are problems in terms of price, and this method does not always provide satisfactory reaction results.

However, there is room for improvement.

Therefore, an object of the present invention is to provide a method for producing Pitami/A with good results using an industrially versatile and inexpensive base.

[Means for Solving the Problems] According to the present invention, the above-mentioned object is:
R1 represents an optionally substituted phenyl group; R2
represents a lower acyl group; A quaternary ammonium salt represented by the general formula (3) (in which 17 , R8 , R9 is the same or different and each represents an alkyl group, an aryl group, or an aralkyl group which may be substituted with a hydrogen atom, an oxygen atom) This is achieved by Aft acylation.

Above - R', R2, X' in formula (υ and (2))
BS, R4, R5, R6 and X will be explained in detail.

R' Vi represents an optionally substituted phenyl group.

Here, the substituents are methyl, ethyl, 1-propyl%
Lower alkyl groups such as n-globyl, l-butyl, n-butyl; halogen atoms such as chlorine, bromine, iodine; and lower alkyl groups such as methoxy, ethoxy, l-propoxy, n-propoxy, 1-butoxy, n-butoxy An example is an alkoxy group.

Further, the substituent may be located at any position such as the ortho position, the meta position, or the -position, and may be one or two or more substituents. R2 represents a lower acyl group such as formyl, acetyl or propionyl.

Xl is different from a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom.

R3, 14, R5 and R6 represent an alkyl group or an aralkyl group. Here, the alkyl group is preferably a linear or branched one with 1 to 20 carbon atoms, and a methyl group, an ethyl group, an n -globyl group, 1-f lopyl group, n
-Gutyl group, (methyl group, hexyl group, heptyl group, octyl group, nonyl group.

Examples include a decyl group, a dobuful group, a tridecyl group, an octadecyl group, and a nonadecyl group. Examples of the aralkyl group include a pencil group, 1-phenylethyl group, 2-phenylethyl group, and 3-phenylethyl group.

and
Examples of lower alkoxy groups include methoxy, ethoxy, glopoxy, n-ethoxy, and t-ethoxy groups, and examples of acyloxy groups include lower alkylcarmenyl such as formyloxy, acetoxy, and glopionyloxy groups. Examples include oxy groups and aryl groups such as benzoyloxy groups.

Specific examples of the quaternary ammonium salt represented by the general formula (2) include chlorinated tetraethylammonium 9m, 45-chlorinated tetraethylammonium 9m, iodinated tetraethylammonium, chlorinated tetra-n-glylammonium, and brominated tetraethylammonium. -n-butylammonium, hydrogenated tetra-n-butylammonium sulfate, tetra-n-butylammonium methoxide, chlorinated pencil trimethylammonium.

Examples include chlorinated stearyltrimethylammonium. The amount of quaternary ammonium salt used is 0.1 to 100 mol relative to the halosulfone represented by general formula (1).
The amount is preferably 1 to Smol.

Examples of the vitamin calgenic acid ester produced by the method of the present invention include vitamin A acetate and vitamin palmitate.

The amount of potassium hydroxide used in the reaction for inducing vitamin A from rosulfone represented by general formula (1) according to the present invention is approximately A fit amount of 2 to 20 moles is preferred. This reaction should preferably be carried out under an inert gas atmosphere in a hydrocarbon solvent or an ether solvent.
Examples of hydrocarbon solvents include toluene, benzene, hexane, and cyclohexane, and examples of ether solvents include tetrahydrofuran, diethyl ether, ngropylether, butyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, and zoethylene glycol. Examples include methyl ether, triethylene glycol methyl ether, and tetraethylene glycol methyl ether.

Among these, the use of tetrahydrofuran is particularly preferred.The solvent is used in an amount such that the concentration of the reaction raw material, rosulfone, is about 0.05 to 2 mol/l, but this numerical range is Not necessarily limited.

R7, R8 and R9 in general formula (3) represent a hydrogen atom, an alkyl group optionally substituted with a # element, an aryl group or an aralkyl group. Examples of the alkyl group include a methyl group, an ethyl group, a globyl group, a butyl group, an inthyl group, and a hexyl group.

Those having 1 to a carbon atoms are preferred. When substituted with an oxygen atom, the alkyl group includes a methoxymethyl group, 2
-methoxyethoxymethyl group, 2-(2-methoxyethoxy)ethoxymethyl group, and the like. Examples of the aryl group include a phenyl group, tolyl group, and xylyl group. Examples include an aral Φ-yl group, a tositehahenzol group, a 1-phenylethyl group, a 12-phenylethyl group, a 3-7enylgropyl group, and the like.

Specific examples of the alcohols represented by the general formula (3) include hamethanol, ethanol, 1-7'lonomol, t-
1-tanol, benzene/tyl alcohol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, etc. Among these, in particular, general formula (4) % formula % (where n is 1, 2 or 3 Preferably, ethylene glycol monomethyl ethers are used. The amount of these alcohols to be used is preferably 0.01 for the halosulfone Klj represented by the general formula (preferably 0.01
The amount is from mol to 30 mol, more preferably from 0.5 mol to 2 mol.

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

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 preferred. After the reaction is completed, the precipitated eyelids are filtered off from the reaction mixture if necessary, and then water, a saline solution, etc. are added to the reaction mixture to completely separate the organic layer. Vitamin A can be obtained by subjecting the obtained organic layer to purification means such as recrystallization and column chromatography.

By acylating the vitamin A thus obtained by a conventional method, it is possible to convert it into calgenic acid ester of vitamin A. This acylation reaction is carried out on the organic layer containing vitamin A separated from the reaction mixture obtained by the above-mentioned vitamin A production reaction or on the vitamin A separated and purified from the organic layer, preferably in an organic solvent.
This is carried out by using an acylating agent in the presence of a tertiary amine or an alkali metal carbonate. Examples of the acylating agent include acetic anhydride, acetyl chloride, f.
Lumitoil etc. are used. The amount of acylating agent to be used is preferably about 1 to 10 parts per vitamin A. Examples of organic solvents include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride, dichloroethane, etc.; ethers such as diethyl ether and noisozorobyl ether; and ethyl acetate and butyl acetate. Esters and the like are used, and it is preferable to use such an organic heating medium that the concentration of vitamin A is about 0.1 to 5 mol/l. As the tertiary amine, for example, triethylamine, pyrinone, etc. are used. These tertiary amino acids 7f'i are about 1 to 1 for vitamin A.
Although it is preferable to use an excess amount, the tertiary amine can also serve as an organic heating medium by using an excess amount. When using an alkali metal carbonate, for example, sodium carbonate, potassium carbonate, lithium carbonate, etc. can be used, and the amount used is preferably 0.1 to 5 equivalents relative to the acylating agent.

Preferably, the reaction is carried out at a temperature range of about -10°C to 50°C. After the reaction is completed, precipitates are filtered from the reaction mixture as necessary, and then dilute sulfuric acid, water, saturated carbonated ice, a water solution, a sodium dredged solution, etc. are added to the reaction mixture, and organic j- is added. To separate. By subjecting the obtained organic layer to IL1 methods such as recrystallization and column chromatography, it is possible to obtain the calcium phosphate ester of vitamin A.

The method for synthesizing halosulfone represented by 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, a compound represented by general formula (5) (wherein R1 is as defined above) and a compound represented by general formula (6) (wherein R2 is as defined above) are combined into Grignard. A hydroxysulfone represented by the general formula (7) (wherein R1 and R2 are as defined above) produced by reacting in the presence of an anionizing agent such as a reagent or an alkyllithium is added with a halogen such as thionyl chloride. It can be produced by applying a curing agent.

〔Example〕

The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Example using tetrahydrofuran solvent HF 1-acetoxy-6-chloro-3,7-nomethyl-9- (2,6,6
−)! J, “F-ru-1-cyclohexen-1-yl)
-9-phenylsulfonyl-2,7-nonadiene 22,
After adding 32 g (44 mmot) and THF75++1j and stirring for a while, chlorinated tetraethylammonium 3704 (1,76 mmot), 2-methoxyethanol 3.341 (44 mmot), potassium hydroxide (purity 95%) 13.9 (220 mmot)
) and stirred at 30°C for 6.5 hours. 100 rr.l of toluene and 50 ml of saline solution were added to the reaction solution, and the mixture was separated.

20.2 rnl (213 mmot) of acetic anhydride was added to this organic layer.
) and 1.819 g of sodium carbonate were added and stirred at 40°C for 3 hours. 10'l of hydroxide water bath solution 20
After adding 0ml to the reaction solution, the organic layer was separated, and this organic J- was washed twice with 100d of brine, and the solvent was distilled off to give a red oily substance of 221! I got it.

When this oily substance was quantified using high performance liquid chromatography, the yield of vitamin A acetate was 1-acetoxy-6-chloro-3,7-tumethyl-9-(2,6
,6-drimethyl-1-cyclohexen-1-yl)-
It was 82.496 based on 9-phenylsulfo, nyl-2,7-nonanonine, and the total trans isomer ratio in vitamin A acetate was 94.6 壬.

Example 2. 1-acetoquine-6-chloro-3,7-nomethyl-9- (2,6,6
-drimethyl-1-cyclohexen-1-yl)-9-
Phenylsulfonyl-2+7-nonanonine 22.32
g (44 mmot) and toluene 100 m/! After stirring vigorously, add 567 mI of tetra-n-butylammonium bromide. (1,76 mmot) methanol 1.411 (44 mmot), potassium hydroxide (
Purity 95%) 13f! (220 mmot) and 40
The mixture was stirred at ℃ for 11 hours. 5 ml of saline solution was added to the reaction solution to separate the layers. To this organic layer, 20.2 ml of acetic anhydride (2
13 mmot) and 1.871 sodium carbonate.
The mixture was stirred at 0°C for 3 hours. After adding 200 #It of IJum aqueous solution to the reaction solution, the organic layer was separated, and this organic layer was further washed twice with 54 room of sodium chloride solution, and the solvent was distilled off. Red oily substance 23.0
I got 19. When this oil was quantified using high performance liquid chromatography, the yield of vitamin A acetate was 1-acetoxy-6-chloro-3,7--/methyl-9-(2,6,6-drimethyl-1-cyclohexene). 79.84 based on -1-yl)-9-phenylsulfonyl-2,7-nonadiene, and vitamin A
The total trans isomer ratio in acetate was 92.096.

〔Effect of the invention〕

According to the method of the present invention, as is clear from the above examples, acetates of vitamins A, -J, etc. can be easily produced in good yield from inexpensive and easily available industrial raw materials.

Patent applicant: RiRashi Co., Ltd.

Claims (1)

[Claims] 1. General formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R^1 represents an optionally substituted phenyl group, and R^2 represents a lower represents an acyl group, and X^1 represents a halogen atom) in a hydrocarbon solvent or an ether solvent. , R^3, R^4, R^5, and R^6 are the same or different and each is an alkyl group or an aralkyl group, and
is a halogen atom, a lower alkoxy group, an acyloxy group,
represents a hydrogen sulfate group or a hydroxyl group) and the general formula (3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3) (In the formula, R^7, R^8, R^9 are the same or different and each represents an alkyl group, an aryl group, or an aralkyl group which may be substituted with a hydrogen atom or an oxygen atom). A method for producing vitamin A or its carboxylic acid ester, which is characterized by acylation. 2. Alcohol represented by general formula (3) is represented by general formula (4)
▲There are mathematical formulas, chemical formulas, tables, etc.▼(4) The method according to claim 1, wherein the ethylene glycol monomethyl ether is represented by the following formula (in the formula, n represents an integer of 1, 2 or 3). 3. The method according to claim 1, wherein the ether solvent is tetrahydrofuran.