GB1591905A - Manufacture of canthaxanthin - Google Patents

Abstract

Canthaxanthin is prepared by oxidation of isozeaxanthin or 4'-hydroxyechinenone with a salt of chloric(V) acid or bromic(V) acid in the presence of a catalyst and of an inert diluent or solvent at temperatures in the range from 0 to 100 DEG C. Suitable catalysts are the halogens bromine and iodine, it also being possible for the catalyst to be formed in situ.

Description

(54) MANUFACTURE OF CANTHAXANTHIN (71) We, BASF AKTIENGESELLSCHAFT, a German Joint Stock Company of 6700 Ludwigshafen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following Statement:- The present invention relates to a process for the manufacture of canthaxanthin.

The product, canthaxanthin, is one of the carotinoid ketones and is mainly used as a foodstuff dye and as a feed additive.

The manufacture of canthaxanthin by oxidizing P-carotin or retro-dehydro-carotin with ammonium metaperiodate or an alkali metal metaperiodate is disclosed in German Patent 1,793,308. The reaction takes place in a two-phase system of water and an inert, water-immiscible solvent in the presence of a catalyst, for example iodine, bromine or an oxide of an element of group Va, VIa, VIIa or VIII of the periodic table. Essential disadvantages of this process are the low yield, which varies from 17 to 38%, and the high cost of the metaperiodate used as the oxidizing agent.

Our copending Patent Application 32,447/76 (Serial No. 1,549,389) describes and claims a process for the manufacture of canthaxanthin by oxidizing P-carotene, retro-dehydro-carotene or echinenone, wherein the oxidation is carried out with chloric or bromic acid or a salt of chloric acid or bromic acid in the presence of chlorine, bromine or iodine or of an oxide or oxo-acid of selenium or of an element of group Va, VIa or VIIa of the periodic table or of a salt of such an oxo-acid or of an oxide of an element of group VIII of the periodic table as a catalyst and in the presence of an inert diluent or solvent at from 0 to 500C.

We have found that canthaxanthin is obtained when isozeaxanthin or 4'-hydroxyechinenone is oxidized with a chloric or bromic acid or salt of chloric acid or of bromic acid in the presence of bromine or iodine or of an oxide or oxo-acid of selenium or of an element of group Va, VIa or VIIa of the periodic table or of a salt of such an oxo-acid or of an oxide of an element of group VIII of the periodic table, as catalyst and in the presence of an inert diluent or solvent, at from 0 to 100"C.

Advantages of the process according to the invention are that the reaction takes place rapidly, the yield is good and the oxidizing agents are readily accessible and cheap.

The starting materials may be used for the oxidation in the form of a dilute solution or of a suspension in a diluent. Advantageously, solution of from 1 to 10 g of starting material per liter of an inert, readily volatile, water-immiscible solvent, or suspensions of the starting material in a diluent - in which case the amount of starting material per liter of diluent can be substantially greater -- are used.

Suitable solvents or diluents are, inter alia, aliphatic chlorohydrocarbons, e.g.

chloroform, methylene chloride, 1,1 -di- chloroethane, 1 ,2-dichloroethane, 1,12-tri- chloroethane, 1,1 ,2,2-tetrachloroethane, 1,2dichloroethylene and 1,1 ,2-trichloroethylene, aromatic hydrocarbons, e.g. benzene, toluene, nitrobenzene and chlorobenzene, dialkyl ethers, e.g. diethyl ether and di-n-propyl ether, or carbon disulfide.

Particularly suitable solvents are chloroform, methylene chloride and nitrobenzene.

Mixtures of these diluents or solvents can also be used.

The oxidizing agent used is a salt of chloric acid or of bromic acid, especially an alkaline earth metal salt, alkali metal salt or ammonium salt, or the free acid.

Advantageously, the oxidizing agent is added to the reaction mixture in the form of an aqueous solution of from 5 to 50% strength by weight. The molar ratio of oxidizing agent to starting material is generally from 1 : 1 to 100 : 1, preferably from 1 : 1 to 20 : 1. The use of more than a 100-fold molar excess of oxidizing agent has no additional effect on the reaction.

The oxidation is catalyzed by bromine and iodine, by oxides and oxo-acids of selenium and of the elements of groups Va, VIa and VIIa of the periodic table, by salts of these oxo-acids, and by oxides of the elements of group VIII of the periodic table. Examples of suitable catalysts are selenium dioxide, selenous acid and its salts, selenic acid and its salts, vanadium pentoxide, vanadates, polyvanadic acids and their salts, heteropolyacids of vanadium, especially with the elements tungsten, molybdenum and phosphorus, and their salts, molybdenum trioxide, molybdates, especially ammonium molybdate, polymolybdates, heteropolyacids of molybdenum, especially with the elements vanadium or phosphorus, tungsten trioxide, tungstates, polytungstic acids and their salts, heteropolyacids of tungsten, especially with the elements vanadium and phosphorus, and their salts, manganese dioxide, nickel oxide and osmium tetroxide. The preferred catalysts are bromine and iodine, iodine being particularly suitable.

The catalyst may be added undiluted or in solution, for example in the solvent which has been used to dissolve the starting material, or in water. The catalyst may also be formcd in situ. The amount of catalyst is advantageously from 0.1 to 10% by weight, preferably from 1 to 5% by weight, based on starting material.

The reaction is carried out at from 0 to 100 C, preferably from 15 to 40"C.

The reaction takes place at a pH ranging from strongly acid values to 7. A pH of from 2 to 6 is preferred. Acids, for example sulfuric acid, hydrochloric acid or acetic acid, or buffer mixtures, may be used to obtain the desired pH.

The reaction time is generally from 1 to 25 hours, depending on the selected conditions. As a rule, less than 2 hours are required to obtain an optimum yield of canthaxanthin.

In order to prevent oxidation of the canthaxanthin by atmospheric oxygen. the reaction can be carried out under an inert gas atmosphere. Examples of gases which are inert under the reaction conditions are argon, neon, helium, carbon dioxide and especially nitrogen.

In a preferred embodiment of the process, an aqueous solution of the oxidizing agent is added, under an inert gas atmosphere, to a solution or a suspension of the starting material in a diluent or solvent which is inert under the reaction conditions and is water-immiscible. The aqueous phase is then brought to the desired pH with an acid or a buffer mixture. After adding the catalyst, as a solid or a solution, the reaction mixture is stirred until a test by thin layer chromatography, carried out in the conventional manner, shows the presence of canthaxanthin only.

The canthaxanthin can either be precipitated by direct addition of methanol or ethanol to the organic phase or be isolated by stripping the diluent or solvent under reduced pressure after the organic phase has been washed with water and dried.

Ethanol or methanol is then added to the crude canthaxanthin to complete its crystallization. After a short time, the canthaxanthin can be separated off.

If desired, the product can be isomerized to the required all-trans-form in the conventional manner, for example by heating the crude product in an organic solvent, for instance an alcohol, e.g. methanol, ethanol, butanol or isobutanol, or an aliphatic hydrocarbon, e.g. heptane, with or without the addition of small amounts of iodine.

EXAMPLE 1 An aqueous solution of 3.2 g of sodium chlorate and 20 mg of sodium iodide in 20 ml of water is added to 500 mg of racemic isozeaxanthin dissolved in 50 ml of chloroform. The two-phase mixture is stirred thoroughly at room temperature and 5 ml of 0.01N sulfuric acid are added. After one hour, the mixture is neutralized with dilute sodium carbonate solution, the phases are separated and the organic solution is washed with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure, 50 ml of heptane are added to the residue and the mixture is boiled for one hour under reflux. After cooling, it is filtered and 471 mg of canthaxanthin, corresponding to a yield of 94% /O of theory, are obtained.

EXAMPLE 2 50 mg of sodium chlorate dissolved in 0.9 ml of water are added to 100 mg of 4'-hydroxyechinenone dissolved in 10 ml of methylene chloride. The mixture is stirred at room temperature and 3 ml of methylene chloride, in which 1 mg of iodine has been dissolved, are added dropwise in the course of 10 minutes. After a further 20 minutes, 4 ml of water are added and the phases are separated. Thin layer chromatography shows canthaxanthin as the sole reaction product. The yield, determined by UV spectroscopy, is 81.3 mg of canthaxanthin.

EXAMPLE 3 1.5 g of sodium bromate dissolved in 20 ml of water are added to 1.5 g of isozeaxanthin, dissolved in 250 ml of 1,2-dichloroethane. 10 ml of 1.2-dichloroethane, in which 30 mg of bromine are dissolved, are added dropwise m the course of 30 minutes, while stirring.

The pH of the aqueous phase is 5.6. The mixture is stirred for 1 hour at room temperature, the phases are separated, the 1,2-dichloroethane phase is washed with sodium bicrabonate solution and water and is dried, and the solvent is distilled off under reduced pressure. 20 ml of methanol are added to the residue and the mixture is stirred for 10 minutes at 50"C. On filtering the mixture after it has cooled, 1.36 g of canthaxanthin, corresponding to a yield of 92% of theory, are obtained.

EXAMPLE 4 1 g of isozeaxanthin, 20 ml of ethylene chloride and 15 ml of water, in which 0.5 g of sodium chlorate and 0.02 g of sodium iodide has been dissolved, are heated to the reflux temperature. The mixture is acidified with 0.04 ml of 1N sulfuric acid, while stirring. After 40 minutes' vigorous stirring and boiling under reflux at 72"C, only canthaxanthin can be detected on a thin layer plate. The aqueous phase is neutralized with dilute aqueous sodium bicarbonate solution and the mixture is allowed to cool. The organic phase is filtered off and washed free from iodine with a dilute solution of sodium bisulfite. It is then washed once with 20 ml of water and dried over magnesium sulfate, after which the ethylene chloride is distilled off under reduced pressure. 8 ml of isopropyl alcohol are added to the residue and the mixture is boiled for 10 minutes under reflux and then left to stand for 10 hours at room temperature. Filtration gives 0.874 g of canthaxanthin, corresponding to a yield of 88%.

WHAT WE CLAIM IS: 1. A process for the manufacture of canthaxanthin, wherein isozeaxanthin or 4'-hydroxyechinenone is oxidized with chloric or bromic acid or a salt of chloric acid or of bromic acid in the presence of bromide or iodine or of an oxide or oxoacid of selenium or of an element of group Va, VIa or VIIa of the periodic table or of a salt of such an oxo-acid or of an oxide of an element of group VIII of the periodic table as catalyst and in the presence of an inert diluent or solvent at from 0 to 100do.

2. A process as claimed in claim 1, wherein the oxidation is carried out with an alkali metal salt of chloric acid or of bromic acid.

3. A process as claimed in claim 1 or 2, wherein the oxidation is carried out at a pH of from 2 to 6.

4. A process as claimed in any of claims 1 to 3, wherein the catalyst is formed in situ.

5. A process as claimed in any of claims 1 to 4, wherein the oxidation is carried out in the presence of iodine as the catalyst.

6. A process as claimed in any of claims 1 to 5, wherein the oxidation is carried out in the presence of a waterimmiscible inert diluent or solvent.

7. A process as claimed in any of claims 1 to 5, wherein the oxidation is carried out in the presence of an aliphatic chlorohydrocarbon as the diluent or solvent.

8. A process for the manufacture of canthaxanthin carried out substantially as described in any of the foregoing Examples.

9. Canthaxanthin when obtained by the process of claim 1.

10. Food, especially animal feed, containing canthaxanthin claimed in claim 9 as a dye or additive.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (10)

**WARNING** start of CLMS field may overlap end of DESC **. is dried, and the solvent is distilled off under reduced pressure. 20 ml of methanol are added to the residue and the mixture is stirred for 10 minutes at 50"C. On filtering the mixture after it has cooled, 1.36 g of canthaxanthin, corresponding to a yield of 92% of theory, are obtained. EXAMPLE 4

1 g of isozeaxanthin, 20 ml of ethylene chloride and 15 ml of water, in which 0.5 g of sodium chlorate and 0.02 g of sodium iodide has been dissolved, are heated to the reflux temperature. The mixture is acidified with 0.04 ml of 1N sulfuric acid, while stirring. After 40 minutes' vigorous stirring and boiling under reflux at 72"C, only canthaxanthin can be detected on a thin layer plate. The aqueous phase is neutralized with dilute aqueous sodium bicarbonate solution and the mixture is allowed to cool. The organic phase is filtered off and washed free from iodine with a dilute solution of sodium bisulfite. It is then washed once with 20 ml of water and dried over magnesium sulfate, after which the ethylene chloride is distilled off under reduced pressure. 8 ml of isopropyl alcohol are added to the residue and the mixture is boiled for 10 minutes under reflux and then left to stand for 10 hours at room temperature. Filtration gives 0.874 g of canthaxanthin, corresponding to a yield of 88%.

WHAT WE CLAIM IS: 1. A process for the manufacture of canthaxanthin, wherein isozeaxanthin or 4'-hydroxyechinenone is oxidized with chloric or bromic acid or a salt of chloric acid or of bromic acid in the presence of bromide or iodine or of an oxide or oxoacid of selenium or of an element of group Va, VIa or VIIa of the periodic table or of a salt of such an oxo-acid or of an oxide of an element of group VIII of the periodic table as catalyst and in the presence of an inert diluent or solvent at from 0 to 100do.

2. A process as claimed in claim 1, wherein the oxidation is carried out with an alkali metal salt of chloric acid or of bromic acid.

3. A process as claimed in claim 1 or 2, wherein the oxidation is carried out at a pH of from 2 to 6.

4. A process as claimed in any of claims 1 to 3, wherein the catalyst is formed in situ.

5. A process as claimed in any of claims 1 to 4, wherein the oxidation is carried out in the presence of iodine as the catalyst.

6. A process as claimed in any of claims 1 to 5, wherein the oxidation is carried out in the presence of a waterimmiscible inert diluent or solvent.

7. A process as claimed in any of claims 1 to 5, wherein the oxidation is carried out in the presence of an aliphatic chlorohydrocarbon as the diluent or solvent.

8. A process for the manufacture of canthaxanthin carried out substantially as described in any of the foregoing Examples.

9. Canthaxanthin when obtained by the process of claim 1.

10. Food, especially animal feed, containing canthaxanthin claimed in claim 9 as a dye or additive.