JPH0217173A - Production of vitamin a or carboxylic acid ester thereof - Google Patents

Abstract

PURPOSE:To readily obtain the subject compound useful as a medicine, feed additive, etc., in good yield from an inexpensive and readily available industrial raw material by treating a halo sulfone, etc., with KOH in the presence of a quaternary ammonium salt in a specific solvent. CONSTITUTION:A halo sulfone expressed by formula I [R<1> is (substituted) phenyl; X<1> is halogen] or vinyl sulfone expressed by formula II is reacted with KOH in a hydrocarbon-based solvent, such as toluene, in the presence of a quaternary ammonium salt expressed by formula III (R<2> to R<5> are alkyl or aralkyl; X is halogen, lower alkoxy, acyloxy, hydrogensulfuric acid group or OH) or a crown ether, such as 12-crown-4, at -10 to +100 deg.C, preferably in an inert gas atmosphere to afford vitamin A, which is then acylated with an acylating agent in the presence of an alkaline metal carbonate, etc., in a solvent to provide a carboxylic acid ester of the vitamin A, such as vitamin A acetate.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing vitamin A or its carcinic acid ester. Vitamin A and its carboxylic acid esters such as acetate and tukulumitate are used in pharmaceuticals and livestock.
It is used in large quantities as an I+ additive.

[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.

Noherosulfone/ [Problems to be Solved by the Invention] According to the conventional method described above, when the reaction raw material halosulfone is treated with potassium alkoxide, vitamin C can be obtained in a relatively good yield. Alkoxides have problems in terms of availability, price, etc. This method is not necessarily satisfactory in terms of reaction volume.

However, there is room for improvement.

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

[Failure to solve the problem]

According to the present invention, the above object is achieved by the general formula (1) (wherein,
R+Fi optionally substituted phenyl group, X
l represents a halogen atom] and/or a vinyl sulfone represented by the general formula (2) (wherein R is as defined above) in a hydrocarbon solvent, the general formula (3) ( In the formula, R2, R5, R' and R are the same or different, each being an alkyl group or an aralkyl group, and X is a halogen atom, a lower alkoxy group, an acyloxy group, a hydrogen sulfate group or a hydroxyl group). This is achieved by treatment with potassium hydroxide in the presence of an ammonium salt or crown ether, and optionally acylating the produced vitamin A.

R', Xl, R2, R' in the above general formula
R4, R5 and X will be explained in detail. R1 represents an optionally substituted phenyl group, where the substituents include methyl, ethyl, j-propyl, n-propyl, l-
Lower alkyl groups such as butyl and n-butyl; halogen atoms such as chlorine, bromine, and iodine; and methoxy, ethoxy, l-propoxy, n-propoxy, l-butoxy, n
Examples include lower alkoxy groups such as -butoxy. In addition, the substituent may be located at any of the ortho-position, meta-position, or 4-position, and may be one or two or more substituents. X is a chlorine atom, a bromine atom, or an iodine atom. Represents a halogen atom such as an atom.

R, R, R and R represent an alkyl group or an aralkyl group. Here, the alkyl group is preferably a linear or branched one having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, a chloropyl group, a l-propyl group, an n-butyl group, and a pentyl group.

Examples include hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, tridecyl group, octadecyl group, and nonadecyl group. Examples of the aralkyl group include benzyl group, 1-phenylethyl group, 2-phenylethyl group, and 3-phenylzolopyl group. X
represents an atom, a lower alkoxy group, an acyloxy group, a hydrogen sulfate group (H3O4-), or a hydroxyl group;
Examples of ron atoms include chlorine, bromine, and iodine, and examples of lower alkoxy groups include methoxy, ethoxy,
Examples include propoxy group, n-butoxy group, t-butoxy group, and examples of acyloxy group include formyloxy group,
Examples include lower alkylcarbinyloxy groups such as acetoxy group and glopionyloxy group, and arylcargenyloxy groups such as yohypenzoyloxy group.

Specific examples of the quaternary ammonium salt represented by the general formula (3) include chlorinated tetraethylammonium, brominated tetraethylammonium, iodinated tetraethylammonium, chlorinated tetra-n-butylammonium, and brominated tetra-n-butyl Ammonium, hydrogenated tetrasulfate
Examples include n-butylammonium, tetra-n-butylammonium methoxide, chlorinated pennortrimethylammonium, and chlorinated stearyltrimethylammonium. The amount of quaternary ammonium salt to be used is determined by the general formula (1
) and 1 or general formula (2)
0.1 to 100 m for vinyl sulfone shown in
o1%, preferably 1 to 5 mo1%.

In addition, the crown ether is a cyclic 41J ether containing a total of 4 or more atoms capable of coordinating to metal ions such as oxygen atoms, nitrogen atoms, and sulfur atoms in the bonding portion forming the ring. For example, 12-crown-4,15-crown-5,18-crown-6, dipenzo-18-crown-6, dicyclohexyl-18-
Examples include Crown-6. The amount of crown ether used is determined by the amount of norosulfone and/or
or 0.1 to 100 mo1%, preferably 1 to 10 mo with respect to the vinyl sulfone represented by general formula (2)
It is the amount of l'J.

The reaction of inducing the vinyl sulfone represented by the general formula (1) and/or the vinyl sulfone represented by the general formula (2) according to the present invention to a vitamin compound is preferably carried out in an inert gas atmosphere and in a hydrogenated solvent. Examples of such solvents include toluene, benzene, hexane,
751ff of cyclohexanat. The amount of the solvent used is preferably such that the concentration of the reaction raw materials, rosulfone and vinyl sulfone, is about 0.05 to 2 mol/l.

By the method of the present invention! Examples of the carmenic acid ester of vitamin A produced include vitamin acetate,
Examples include vitamin A and lumitate.

This reaction can be carried out within a temperature range of -10°C to 100°C, but a temperature range of 0 to 40°C is particularly preferred.

The amount of potassium hydroxide used in this reaction is preferably 1% per rosulfone and/or vinylsulfone.
The amount is 20 to 20 moles, more preferably 5 to 7 moles. After the reaction is completed, a precipitate is filtered from the reaction mixture as required, and then water, a saline solution, etc. are added to the reaction mixture, and the organic layer is separated. Vitamin Afc 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, a carboxylic acid ester of vitamin A can be derived. This acylation reaction is performed on the vitamin A separated from the reaction mixture obtained by the above-mentioned vitamin A production reaction and the organic layer containing the vitamin A, or on the vitamin A separated 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. As the acylating agent, for example, acetic anhydride, acetyl chloride, cermidoyl chloride, etc. are used. The amount of the acylating agent used is preferably about 1 to 10 equivalents relative to vitamin A. Examples of organic solvents include hydrocarbons such as benzene and toluene;
Rhodanized hydrocarbons such as methylene chloride and 1,2-dichloroethane; ethers such as zoethyl ether and diisozorobyl ether; and esters such as ethyl acetate and ethyl acetate are used, and these organic solvents It is preferable to use an amount such that the concentration of vitamin A is about 0.1 to 5 mol/l. As the tertiary amine, for example, triethylamine, pyricine, etc. are used. These tertiary amines are preferably used in an amount of about 1 to 10 equivalents relative to vitamin A, but by using an excess amount, the tertiary amines can also serve as an organic solvent. When using 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 based on 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, the precipitate is filtered from the reaction mixture if necessary, and then dilute sulfuric acid, water, saturated aqueous sodium bicarbonate solution, aqueous sodium hydroxide solution, etc. are added to the reaction mixture, and the organic layer is separated. By subjecting the obtained organic layer to purification means such as recrystallization and column chromatography, vitamin A calcium ester can be obtained.

The method for synthesizing halosulfone and/or vinylsulfone, which are raw materials in the present invention, is produced according to the method described in JP-A-62-87559. That is,
- a compound represented by formula (5) (wherein R1 is as defined above) and a compound represented by general formula (6) (wherein R6 represents a lower acyl group) using a Grignard reagent; Hydroxysulfo/thionyl chloride or the like represented by the general formula (7) (wherein R1 and R6 are as defined above) is produced by reacting K in the presence of an anionizing agent such as alkyl lithium. General formula (8) (in the figure, R' r R
' is as defined above;
The halosulfone represented by 1) and the vinyl sulfone represented by general formula (2) can be produced selectively, respectively, or they can be produced as a mixture. According to the present invention, it is possible to derive vitamin A from these rosulfone and vinyl sulfone in good yields, and it is also possible to derive vitamin A in good yields even when these compounds are used as a mixture. I can do it.

〔Example〕

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

Example 1 6-chloro-1- was added to a 2001R1 flask purged with nitrogen.
Hydroxy-3,7-tumethyl-9- (2,6,6-
Dolimethyl-1-cyclohexen-1-yl)-9-7
enylsulfonyl-2,7-nonazoene9,29 fj
(20 mmol), add Toluev 40 at,
After stirring for a while, powdered potassium hydroxide (95%
purity) 5.89 jp (100 mmol) and tetraethylammonium chloride 66.319 (0.4 m
mol) was added and stirred at 10°C for 12 hours. 50#Il of saline solution was added to the reaction solution to separate the layers. To this organic layer were added 1011 (105.4 mmol) of acetic anhydride and 0.99 of sodium carbonate, and the mixture was stirred at 40°C for 3 hours. 1
After adding 100 txl of IJum aqueous solution (100 txl of 0% hydroxide) to the reaction solution, separate the organic layer, wash this organic layer twice with 100ml of 5% brine, and distill off the solvent. 12.8 g of a redder oil was obtained. When this oily substance was quantified using 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-3,7-nomethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6,8- was placed in a 200 ytl flask purged with nitrogen. Nonatriene 8.56g (20
5. Add 49 ml of toluene (mmol) and stir for a while, then add powdered potassium hydroxide (95% purity).
89 g (Zoo mmol) and 66.3 W (0.4 mmol) of chlorinated tetraethylammonium were added and stirred at 10° C. for 12 hours. Add 5% saline to the reaction solution
IIll was added and the mixture was separated. Add 101 ml of acetic anhydride to this organic layer.
11 (105.4 mmol) and sodium carbonate 0.
9 g was added and stirred at 40°C for 3 hours. After adding 100 mj of a 10% aqueous sodium hydroxide solution to the reaction solution, the organic layer was separated, and this organic layer was further diluted with 100 mj of brine.
By washing twice with When this oily substance was quantified using high performance liquid chromatography, the yield of vitamin A acetate was 78.9%.

In addition, the total trans isomer ratio in vitamin A acetate is 94.
．． It was 3%.

Example 3 6-rioo-hydroxy-3,7-nomethyl-9-(2,6,6-trimethyl-l-cyclohexen-1-yl)-9-7enylsulfonyl-2 was added to a 200 at flask purged with nitrogen. , 7-nonadiene 2.6 g (5,6
mmol) and 1-hydroxy-3,7-nomethyl-
9-(2,6,6-)dimethyl-1-fuclohexen-1-yl)-9-phenylsulfonyl-2,6,8-
4 Q ml of toluene was added to a mixture of 6.169 (14.4 mmol) of nonatoluene, and after stirring for a while, powdered potassium hydroxide (95% purity) 5.89
, 9 (100 mmol) and chlorinated tetraethylammonium 66.3"? (0.4 mmol),
The mixture was stirred at 10°C for 12 hours. Add 5Q salt solution to the reaction solution 5Q*
1 was added and the liquid was separated. This organic layer was added with acetic anhydride 10R1 (1
05.4 mmol) and 0.9 g of sodium carbonate were added, and the mixture was stirred at 40°C for 3 hours. 10% hydroxide) IJ
After adding 1,001 g of aqueous solution of 1,001 g of umum to the reaction solution, the organic layer was separated, and this organic layer was further washed twice with 100 tons of brine, and the solvent was distilled off to obtain a red oily substance 12.3
I got g. When this oily substance was quantified using high performance liquid chromatography, the yield of vitamin A acetate was 7.
7.9%, and the total trans isomer ratio in vitamin A acetate was 94.5%.

Example 4 6-chloro-1-hydroxy-3,7-nomethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7- was placed in a 200-gof flask purged with nitrogen. Nona Jien 2, 69 (5,
6 mmol) and 1-hydroxy-3,7-nomethyl-9-(2,6,6-)dimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6,8-
nonatriene 6,16, lil (14,4 mmol
) Add 40 ml of toluene to the mixture and stir for a while, then add powdered potassium hydroxide (95% purity) 5.8
9 g (100 mmol) and 12-crown-471
89 (0.4 mmol) was added and stirred at 10°C for 12 hours. 501 Lt of 5-saline solution was added to the reaction solution and the mixture was separated. To this organic layer was added 10 d of acetic anhydride (105,4 mmo
l) and 0.9 g of sodium carbonate, and heated at 40°C.
Stir for hours. 10% sodium hydroxide aqueous solution 100
After mt was added to the reaction solution, the organic layer was separated, and this organic layer was further washed twice with 100 R1 of 5-chloride solution, and the solvent was distilled off to obtain red oil-filled products 13 and 19. When this oil was quantified using high performance liquid chromatography, the yield of vitamin A7 acetate was 78.2%, and the total trans isomer ratio in vitamin A acetate was 93.8%. [Effects] According to the method of the present invention, as is clear from the above examples, vitamins and their acetates can be easily produced in good yield from industrial raw materials that are inexpensive and easily available.

Patent applicant: RiRashi Co., Ltd.

Claims (1)

[Claims] General formula (1) ▲Mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, R^1 represents an optionally substituted phenyl group, and X^1 represents a halogen atom. ) Halosulfone and/or general formula (2) ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) (In the formula, R^1 is as defined above) In a hydrocarbon solvent, general formula (3) ▲ Mathematical formulas, chemical formulas, tables etc. ▼(3) (In the formula, R^2, R^3, R^4 and R^5 are the same or different and are each an alkyl group or an aralkyl group, and X is a halogen atom, a lower alkoxy group, an acyloxy group , representing a hydrogen sulfate group or a hydroxyl group) or a crown ether (representing a hydrogen sulfate group or a hydroxyl group).
A method for producing vitamin A or its carboxylic acid ester, which comprises acylating vitamin A or its carboxylic acid ester.