KR19990069186A - Method for producing beta carotene - Google Patents

Abstract

The present invention relates to a method for producing beta carotene, more specifically 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8 Nonatetraen-1-oxyl acetate or 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) by adding at least 30 equivalents of triphenylphosphine and sulfuric acid to an alcohol solution at -60 ° C ) -2,4,6,8-nonatetraene-1-oxy triphenylphosphonium hydrosulfate was prepared, and the reaction temperature was lowered from 0 to -20 ° C and then 3,7-dimethyl-9- (2,6 The present invention relates to a method for producing beta carotene, which comprises adding, 6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-al.

According to the present invention, it is possible to provide a method for preparing beta carotene, which shortens the reaction time in preparing beta carotene, simplifies the condensation reaction and purification, and improves the yield and purity.

Description

Method for producing beta carotene

The present invention relates to a method for producing beta carotene, more specifically 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8 Nonatetraen-1-oxyl acetate or 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1 It relates to a method for producing trans beta carotene (trans-β-carotene) simply and efficiently from the All-Bitch reaction.

Beta-carotene, one of the carotenoids widely present in nature, is a precursor of vitamin A without excess and is widely used as a medicine because it has physiological activities such as antioxidant activity, cataract prevention, and photosensitivity treatment. It is a substance that is increasingly being used as a colorant or as a nutritional enhancer of food or feed.

Beta carotene can be artificially synthesized, and various methods of preparing beta carotene are known.

Among the known methods, the method for preparing beta carotene from acetone or acetylene through beta ionone (β-ionone) is a method of producing 8 to 10 steps, which is complicated in manufacturing steps [Pure & Appl. Chem., 51 P447-462 (1979).

3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-al via Wittig reaction And 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytriphenylphosphonium chloride with 0 Method for producing beta carotene by reacting at ℃, 1) 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nona The reaction time is long (about 24 hours) to prepare tetraene-1-oxytriphenylphosphonium chloride, and 2) beta carotene obtained after condensation is subjected to complex purification steps such as filtration, extraction, washing, drying, distillation and isomerization. And 3) the purity and yield of the material obtained are relatively low (purity: 86%, yield: 65%), which is disadvantageous [German Patent No. 1,068,709].

6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene-1 via Wittich reaction -Al and 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytriphenylphosphonium hydro The method of preparing beta carotene by condensing the sulfate at room temperature and treating with base is as follows: 1) 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2 After preparing 4,6,8-nonatetraene-1-oxytriphenylphosphonium hydrosulfate, methanol is distilled off and then dissolved in water to proceed the condensation reaction. Purity and yield of the material obtained after the condensation reaction are low (purity: 41%, yield: 60.2%), and 3) the obtained material must be treated under a base to remove chlorine and phenylsulfonyl groups, thereby obtaining desired beta carotene. The overall reaction stage is longer There are disadvantages, such as Japanese Patent No. Hei 8-19088 (1990).

The present inventors have studied to solve the problems of the prior art as a result, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6, 8-nonatetraen-1-oxyl acetate or 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene- The present invention has been found to be able to prepare trans beta carotene (trans-β-carotene) simply and efficiently from the 1-ol Bitich reaction.

Accordingly, an object of the present invention is to shorten the reaction time, simplify the condensation reaction and purification process, and provide a method for preparing beta carotene with improved yield and purity.

The present invention is a method for producing beta carotene, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene- Alcohol solution of 1-oxyl acetate or 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-ol 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4 by adding at least 30 equivalents of triphenylphosphine and sulfuric acid at a reaction temperature of 30 to 60 캜. , 6,8-nonatetraene-1-oxy triphenylphosphonium hydrosulfate was prepared, and the reaction temperature was lowered from 0 to -20 ° C, followed by 3,7-dimethyl-9- (2,6,6-trimethyl- It is a method for producing beta carotene, characterized by adding 1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-al.

Hereinafter, the present invention will be described in more detail.

In the present invention, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-oxyl acetate is converted into methanol, In an alcoholic solvent such as ethanol, 3,7-dimethyl-9- (2,6) was reacted with 30 equivalents of triphenylphosphine and 20 to 60% sulfuric acid dissolved in alcohol for 1 to 5 hours at 30 to 60 캜. Prepare, 6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytriphenylphosphonium hydrosulfate. When reaction temperature is lower than 30 degreeC, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1 -The reaction time for preparing oxytriphenylphosphonium hydrosulfate is longer than 15 hours, when the reaction temperature is higher than 60 ℃, 3,7-dimethyl-9- which is an unstable starting material for oxygen, light, heat, etc. (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxyl acetate or 3,7-dimethyl-9- (2,6 produced , 6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytriphenylphosphonium hydrosulfate is decomposed and side reactions occur, resulting in poor synthetic yields.

Preparation of 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytriphenylphosphonium hydrosulfate After completion of the reaction, the temperature of the reactor was lowered to 0 to -20 ° C without removing or replacing the solvent, and then 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl)- 2,4,6,8-nonatetraen-1-al is added. Two equivalents or more of caustic soda or caustic dissolved in methanol or ethanol at the same temperature is slowly added and then aged at the same temperature for 1 to 8 hours. When the reaction temperature is higher than 0 ℃ a lot of side reactions proceed, if it is too low below -20 ℃ has the disadvantage that it takes more than 20 hours to terminate the condensation reaction.

The simplified purification of beta carotene produced after the reaction is as follows.

Hydrocarbon solvents such as benzene and toluene, halo hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran, esters such as ethyl acetate and butyl acetate A solvent or the like is added to the reaction solution to dissolve beta carotene, washed with warm water to remove impurities, and the solvent is removed under reduced pressure to obtain crude beta carotene. Crude beta carotene consists of cis beta carotene and trans beta carotene.

Water was added to the obtained beta carotene and stirred at 90 to 100 ° C. for 3 to 20 hours to isomerize the cis beta carotene to obtain trans beta carotene. After completion of the isomerization reaction, the reaction temperature is lowered to room temperature, cooled, and the solvent is removed by filtration to obtain wet trans beta carotene. Since the obtained trans-beta carotene is agglomerate, this solid is stirred in a non-alcoholic polar solvent such as acetone or MEK (methyl ethyl ketone) for 30 minutes to 3 hours to form a small solid particle. The obtained solid is filtered and dried under reduced pressure to obtain trans beta carotene in a content (98% or more) that meets food standards.

In the present invention, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytriphenylphospho By preparing the nium salt in the form of hydrosulfate, the hassle of filling hydrochloric acid gas with alcohol is eliminated, and 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4 By preparing phosphonium salts from, 6,8-nonatetraene-1-oxyl acetate at temperatures above room temperature, the time for preparing phosphonium salts is significantly shortened (within 5 to 18 hours to 18 hours), 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1 without separation or solvent removal The condensation reaction is simplified by reacting with eggs, and the method for purifying beta carotene is simple by hot water washing, distillation under reduced pressure, and isomerization, and a method and method for preparing beta carotene with improved synthetic yield and purity have been developed.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-al was obtained from BASF, Hydrolysis of 7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxyl acetate (2.8MIU / g) Synthesis was carried out through the reaction and oxidation reaction, and solvents were used for industrial use and alcohol for drugs.

49.2 g (2.8) of 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxyl acetate in a nitrogen atmosphere MIU / g, 0.15 mole) was dissolved in 155 g of ethanol, and stirred in a reactor. 52 g of triphenylphosphine was added and the temperature of the reactor was raised to 40 ° C. with stirring. Slowly inject 60 g of 35% sulfuric acid-ethanol solution and stir at 40 ° C. for 3 hours to give 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4 , 6,8-nonatetraene-1-oxytriphenylphosphonium hydrosulfate was prepared. Cool the reactor temperature to -15 ° C and synthesize 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetra 45 g (˜98%) of EN-1-al were added to the reactor. 440 g of 2.5N caustic ethanol solution was slowly added while maintaining the temperature at -15 to -10 ° C and aged for 3 hours. 1500 ml of toluene was added to the reaction mixture, followed by mixing 2000 ml of warm water, stirring and washing for 10 minutes, and then separating the water layer. The organic layer was distilled off under reduced pressure to obtain crude beta carotene.

The crude beta carotene was washed with 500 ml of ethanol and 2500 ml of water, and then 650 ml of water was added under a nitrogen atmosphere and stirred at 96 to 100 ° C. for 5 hours. After the mixture was cooled to room temperature, the solvent was removed, and 250 ml of acetone was added to the solid, followed by stirring for 1 hour, followed by filtration. It was washed with a small amount of acetone and dried under reduced pressure to obtain 65 g (81%) of trans beta carotene with a content of 98.9% (measured by UV spectrometer).

Example 2

Using the same conditions and reagents as in Example 1, but using methanol instead of solvent ethanol, 62 g (77.3%) of trans beta carotene of 98.4% (measured by UV spectrometer) was obtained.

Example 3

The same conditions and reagents as in Example 1 were used, but instead of the acetone washing in the last step, purification was carried out with ethanol and dried under reduced pressure to obtain 64.5 g (80.4%) of trans beta carotene of 98.7% (measured by UV spectrometer).

Example 4

In 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxyl acetate (2.8MIU / g) 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-ol, previously synthesized by hydrolysis 42.9 g (0.15 mol) was dissolved in 155 g of ethanol, put in a reactor, and stirred in a nitrogen atmosphere. 52 g of triphenylphosphine were added and the temperature of the reactor was raised to 50 ° C. with stirring. Slowly inject 70 g of 30% sulfuric acid-ethanol solution and stir at 50 ° C. for 2 hours to give 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4 , 6,8-nonatetraene-1-oxytriphenylphosphonium hydrosulfate was prepared. Cool the reactor temperature to -15 ° C and synthesize 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetra 45 g (˜98%) of EN-1-al were added to the reactor. 440 g of 2.5N caustic / ethanol solution was slowly added while maintaining the temperature of the reactor at -15 to -10 ° C and aged for 3 hours. 1500 ml of toluene and 2000 ml of warm water were added to the reaction solution, followed by stirring and washing for 10 minutes, and then the water layer was separated. The organic layer was distilled off under reduced pressure to obtain crude beta carotene. The crude beta carotene was washed with 500 ml of ethanol and 2500 ml of water, and then 650 ml of water was added under a nitrogen atmosphere and stirred at 96 to 100 ° C. for 5 hours. After the mixture was cooled to room temperature, the solvent was removed, and 250 ml of acetone was added to the solid, followed by stirring for 1 hour, followed by filtration. After washing with a small amount of acetone and dried under reduced pressure to obtain 63g (78.5%) of trans beta carotene content of 98.5% (measured by UV spectrometer).

Example 5

Using the same conditions and reagents as in Example 4 but using methanol instead of solvent ethanol, 61 g (76%) of trans beta carotene with a content of 98.1% (as measured by UV spectrometer) was obtained.

Example 6

The same conditions and reagents as in Example 4 were used, but 63.5 g (79.1%) of trans beta carotene of 98.6% (measured by UV spectrometer) was obtained by washing with ethanol and drying under reduced pressure instead of acetone washing in the last step in the purification process.

Comparative Example 1

React 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytriphenylphosphonium hydrosulfate Beta carotene was prepared in the same manner as in Example 1 except that the temperature was prepared at 75 ° C.

As a result, 45 g (56%) of trans beta carotene with a content of 98.1% (as measured by UV spectrometer) was obtained.

Comparative Example 2

In 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxyl acetate (2.8MIU / g) 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-ol 42.9 previously synthesized by hydrolysis reaction 60 g of g (0.15 mol) and 52 g of triphenylphosphine were added thereto, followed by stirring in a nitrogen atmosphere. 40 ml of 5N ethanol-hydrochloric acid solution prepared by slowly dissolving hydrochloric acid gas at room temperature was added. The mixture was stirred for 24 hours to give 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxytri Phenylphosphonium chloride was prepared. 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6, dissolved in 55 ml of 4N ethanol-base solution and 35 ml of anhydrous ethanol in the obtained solution 35 g of 8-nonatetraen-1-al were added simultaneously and cooled to lower the temperature to 0 ° C. After stirring for 2 hours, the beta carotene was filtered and the filtrate was extracted by adding 500 ml of cyclohexane and 30 ml of water. The combined filtrate and extracts were washed with water and the solvent was distilled off. Dissolved with 40 ml of hot benzene, precipitated with 700 ml of ethanol, and filtered and dried to obtain 52 g (65%) of trans beta carotene of 86% (measured by UV spectrometer).

3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-oxyl acetate or 3, according to the invention Beta-carotene was prepared via a Wittich reaction from 7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-ol By shortening the reaction time, simplify the condensation reaction and purification process, it is possible to provide a method for producing beta carotene improved yield and purity.

Claims (3)

In the method for producing beta carotene, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraene-1-oxyl 30 to an alcohol solution of acetate or 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-ol 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6, by adding at least 60 equivalents of triphenylphosphine and sulfuric acid at a reaction temperature of 8-nonatetraene-1-oxy triphenylphosphonium hydrosulfate was prepared, and the reaction temperature was lowered from 0 to -20 ° C, followed by 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclo A method for producing beta carotene, characterized by adding hexen-1-yl) -2,4,6,8-nonatetraen-1-al. The method of claim 1, wherein triphenylphosphine and sulfuric acid are added in the reaction temperature range of 35 to 45 ℃. The compound of claim 1, wherein 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraen-1-al is- Method for producing beta carotene, characterized in that it is added in the reaction temperature range of 15 to -5 ℃.