DE102004012577A1 - Process for the preparation of astaxanthin - Google Patents

Abstract

The invention relates to a process for the preparation of astaxanthin of the formula I DOLLAR F1 by reacting 2 mol of the triphenylphosphonium salt of the general formula II, DOLLAR F2 in which X is chlorine, bromine or the (HSO 4) · - · radical, in a Wittig Reaction with one mole of the C¶10¶-dialdehyde of the formula III, DOLLAR F3, characterized in that DOLLAR A A. the starting compounds of the formulas II and III in one or more solvents selected from the group consisting of ethylene glycol monomethyl ether, 1 -Methoxy-2-propanol and compounds of the general formula R · 1 · -O- (CH¶2¶) ¶2¶-O- (CH¶2¶) ¶2¶-OR · 2 · IV, in which the substituents independently of one another have the following meaning: DOLLAR AR · 1 · hydrogen, C¶1¶-C¶4¶-alkyl; DOLLAR AR · 2 · C¶1¶-C¶4¶-alkyl, C (= O) -C¶1¶-C¶4¶-alkyl is suspended, the suspension is heated to temperatures of 30 to 90 ° C, until has formed a homogeneous solution, DOLLAR A B. the homogeneous solution obtained at temperatures from 0 to 40 ° C. with 1 to 1.2 moles per mole of triphenylphosphonium salt of a base customary for Wittig reactions added and DOLLAR A C. the in process B. precipitated astaxanthin at temperatures of 90 to 130 ° C. under normal pressure in one or more of the solvents mentioned under A. isomerized and then isolated.

Description

The invention relates to an improved process for preparing the C ₄₀ carotenoid astaxanthin by a double Wittig reaction of a 3-methyl-5- (2,6,6-trimethyl-3-oxo-4-hydroxy-1-cyclohexene-1 yl) -2,4-pentadienyl-triphenylphosphonium salt (Asta-C ₁₅ -triphenylphosphonium salt) with 2,7-dimethyl-2,4,6-octatriene-1,8-dial (C ₁₀ -dial).

Astaxanthin is a natural dye very popular for dyeing foods, salmon and trout. Accordingly, numerous methods for isolating or synthesizing astaxanthin are known. For example, the isolation of astaxanthin by extraction of crustacean shells is known from WO 86/6082. Furthermore, astaxanthin can be obtained by fermentative processes (see Biotechnol Letters 10 (1988), 609-614 or from microalgae (see WO 89/1977 and WO 99/18077) EP 329 754 ) be won.

These However, methods have crucial disadvantages. For one thing, Astaxanthin in nature only in very low concentration and therefore must be isolated by complex processes. On the other hand, only achieved unsatisfactory yields. Besides, the big quantities at needed Excipients and accumulated non-recyclable waste ecologically and economically unacceptable.

Of the processes for the synthetic preparation of astaxanthin, the oxidation of canthaxanthin bis-silyl enol ethers with percarboxylic acids and subsequent hydrolysis (cf. EP 101 597 ) called. Disadvantages of this process are the only moderate yields and purities of astaxanthin, imperfect conversions and undesired by-products, such as adonirubin.

Out EP 440,037 Another method for the oxidation of canthaxanthin enolates is known. However, this process is also unsuitable for industrial production, since expensive bases such as the salts of hexamethyldisilazane and very low temperatures are necessary for the preparation of the enolates and the poorly available and safety-explosive phenylsulfonyloxaziridine is used as the oxidizing agent. In addition, the sales is only incomplete in this process.

Out EP 005 749 is a method for the production of astaxanthin by Wittig reaction of an acylated at the hydroxy group in the 4-position of the asta-C ₁₅ -Triarylphosphoniumsalzes blocks with C ₁₀ -dial and subsequent hydrolysis known. The solvent used for this Wittig reaction is, inter alia, called isopropanol. A disadvantage of this process is that protective groups have to be introduced into the C ₁₅ -triphenylphosphonium salts and have to be split off again, as well as the moderate yields achieved.

In EP 005 748 describes the Wittig reaction of Asta-C ₁₅ triarylphosphonium salts, even with C ₁₀ -dial. Suitable solvents are halohydrocarbons, such as methylene chloride and chloroform. A disadvantage of this method is that both as a solvent and for workup by extraction requires large amounts of halogenated hydrocarbons, which are known to have questionable toxicological properties and require a technically complex recovery.

EP 0 733 619 relates to a process for the preparation of astaxanthin, in which the Wittig reaction in methanol and / or ethanol and the subsequent isomerization of the astaxanthin formed in a C _{1 to} C ₄ alkanols is performed. By using the low-boiling alcohols, it is necessary to carry out the isomerization in printing apparatus, which means an increased technical complexity in the synthesis of astaxanthin.

Furthermore, several publications in Helv. Chim Acta, 64 (1981, pages 2405-18, pages 2436-46 and pages 2447-62) describe the reaction of asta-C ₁₅ -triarylphosphonium halides with the C ₁₀ -dial according to Wittig , In all Wittig reactions described methylene chloride is used as a solvent for the phosphonium salts and the C ₁₀ -dialdehyde and methylene chloride used in the workup and purification.

It was therefore an object of the invention to improve the process for the preparation of astaxanthin from an asta-C ₁₅ -Triarylphosphoniumsalz and the C ₁₀ -dialdehyde in a Wittig reaction so that the reaction in a technically simple manner without use aufbewender difficult Can carry out solvent mixtures.

It has now surprisingly been found that one can produce astaxanthin in a technically simple manner and in very good yields, if both for the Wittig reaction as well as for the closing isomerization / workup used the solvent mentioned in claim 1.

durch Umsetzen von 2 Mol des Triphenylphosphoniumsalzes der allgemeinen Formel II

in der X für Chlor, Brom oder den (HS04)^--Rest, vorzugsweise für Brom steht, in einer Wittig-Reaktion mit einem Mol des C₁₀-Dialdehyds der Formel III,

das dadurch gekennzeichnet ist, dass man

• A. die Ausgangsverbindungen der Formeln II und III in einem oder mehreren Lösungsmitteln, ausgewählt aus der Gruppe, bestehend aus Ethylenglykolmonomethylether, 1-Methoxy-propanol-2 und Verbindungen der allgemeinen Formel IV R¹-O-(CH₂)₂-O-(CH₂)₂-O-R² IV,in denen die Substituenten unabhängig voneinander folgende Bedeutung haben: R¹ Wasserstoff, C₁-C₄-Alkyl; R² C₁-C₄-Alkyl, C(=O)-C₁-C₄-Alkyl, suspendiert, die Suspension auf Temperaturen von 30 bis 90°C erwärmt bis sich eine homogene Lösung gebildet hat,
• B. die erhaltene homogene Lösung bei Temperaturen von 0 bis 40°C mit 1 bis 1,2 Mol pro Mol Triphenylphosphoniumsalz einer für Wittig-Reaktionen üblichen Base versetzt und
• C. das im Verfahrensschritt B. ausgefallene Astaxanthin bei Temperaturen von 90 bis 130°C, vorzugsweise 80 bis 100°C unter Normaldruck in einem oder mehreren der unter A. genannten Lösungsmittel isomerisiert und anschließend isoliert.

The invention therefore provides a process for the preparation of astaxanthin of the formula I.

by reacting 2 mol of the triphenylphosphonium salt of the general formula II

radical, preferably bromine, in a Wittig reaction with one mole of C ₁₀ -Dialdehyds of formula III ^- in which X is chlorine, bromine or (HS04)

which is characterized in that one

• A. the starting compounds of formulas II and III in one or more solvents selected from the group consisting of ethylene glycol monomethyl ether, 1-methoxy-2-propanol and compounds of general formula IV R ^{1 is} -O- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OR ² IV, in which the substituents independently of one another have the following meaning: R ^{1 is} hydrogen, C ₁ -C ₄ -alkyl; R ^{2 is} C ₁ -C ₄ -alkyl, C (= O) -C ₁ -C ₄ -alkyl, suspended, the suspension is heated to temperatures of 30 to 90 ° C until a homogeneous solution has formed,
• B. the homogeneous solution obtained at temperatures of 0 to 40 ° C with 1 to 1.2 moles per mole of triphenylphosphonium salt of a conventional base for Wittig reactions and added
• C. the astaxanthin precipitated in process step B. is isomerized at temperatures of 90 to 130 ° C., preferably 80 to 100 ° C. under normal pressure in one or more of the solvents mentioned under A. and subsequently isolated.

Among C ₁ -C ₄ alkyl radicals for R ¹ and R ² are methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert. Butyl to understand.

The radical C (= O) -C ₁ -C ₄ -alkyl represents acyl radicals, for example acetyl or propionyl. Typical representatives of this class of compounds are C ₂ H ₅ O- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OC (= O) CH ₃ or C ₄ H ₉ O- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OC (= O) CH ₃ .

Preferred solvents are ethylene glycol monomethyl ether, 1-methoxy-2-propanol and / or methyl diglycol of the formula CH ₃ O- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OH.

to execution the reaction of the invention In general, one uses so much solvent that the concentration the triphenylphosphonium halides in the alkanol 0.1 to 3 mol, preferably 0.3 to 1 mole per liter of solvent is.

For complete dissolution of the educts of the formulas II and III, the procedure is generally such that they are introduced into the solvent in any desired order and the suspension is heated to 30 to 90.degree heated preferably 40 to 80 ° C.

In some cases It may be beneficial to use the above solvents in a mixture with halogenated hydrocarbons, for example with dichloromethane or chloroform.

In the resulting solution is generally at temperatures of 0 to 40 ° C, preferably 20 to 40 ° C slowly added the base and the reaction mixture in this Temperature stirred. In the case of a mixture of the solvents used in the invention with halocarbons is the preferred temperature range at 0 to 20 ° C.

When for Wittig reactions suitable bases may be mentioned: solutions of alkali or alkaline earth alkoxides or alkali or alkaline earth metal hydroxides in methanol or ethanol, alkali or alkaline earth hydroxides, ammonia, Triethylamine and alkali or alkaline earth carbonates. Designed especially advantageous The process, when an aqueous solution of NaOH or KOH, a methanolic sodium methoxide solution or an ethanolic sodium ethoxide solution.

The Reaction times for the release the starting materials and entering the bases and implementation are generally 0.5 to 12 hours, preferably 1 to 8 hours, more preferably 1.5 to 4 hours.

The isomerization of astaxanthin following the Wittig reaction takes place at temperatures of 90 to 130 ° C, preferably 80 to 100 ° C under atmospheric pressure.

The Isomerization times amount to 0.5 to depending on the reaction temperature 16 hours, preferably 1 to 10 hours, more preferably 2 to 5 hours.

With particular advantage of the inventive method succeeds when the Astaxanthin-containing reaction mixture prior to thermal isomerization with acetic acid neutralized because the oxygen functions in the ring of astaxanthin are more sensitive in alkaline medium.

To the isomerization, the reaction mixture to temperatures of 10 to 50 ° C, preferably 20 to 40 ° C cooled.

The Crystallized astaxanthin is obtained by filtration or centrifugation isolated and with methanol, ethanol and / or mixtures of these alkanols and washed with water.

With Help of the method according to the invention can Astaxanthin coveted as a food dye in yields up to 85% of theory and with selectivities to the all (E) configuration up to 99%.

The according to the inventive method Astaxanthin obtained is characterized inter alia by the fact that it in coarse crystalline form with low filtration resistance accrues.

Based The following examples illustrate the process according to the invention.

example 1

60 g (0.104 mol) of 3-methyl- (2,6,6-trimethyl-3-oxo-4-hydroxy-1-cyclohexen-1-yl) -2,4-pentadienyl-triphenylphosphonium bromide (Asta-C ₁₅ -triphenylphosphonium bromide ) and 7.8 g (0.0476 mol) of 2,7-dimethyl-2,4,6-octatriene-1,8-dial (99 wt%, all-E / 4Z = 2/1) suspended at 25 ° C in 190 ml of ethylene glycol monomethyl ether under inert gas. It was heated to 45 ° C, resulting in a homogeneous solution. After 30 mi nütigem stirring at 45 ° C was cooled to about 25 ° C and added within 20 minutes 7.5 g (0.11 mol) of sodium in 22.5 g of methanol. Subsequently, the reaction mixture was stirred at 30 ° C for 2 hours.

After addition of 3 g (0.05 mol) of glacial acetic acid, the reaction mixture was heated to 100 ° C and stirred at this temperature for 4 hours. After cooling to room temperature (23 ° C), the precipitated astaxanthin was filtered off, washed with about 800 ml of 40 ° C warm methanol and 400 ml of 70 ° C warm water and dried at 50 ° C in a drying oven under inert gas.
Yield: 23.3 g (82.2% of theory), purity 97% (determined by HPLC).

Example 2

60 g (0.104 mol) of 3-methyl- (2,6,6-timethyl-3-oxo-4-hydroxy-1-cyclohexen-1-yl) -2,4-pentadienyl-triphenylphosphonium bromide (asta-C ₁₅ -triphenylphosphonium bromide ) was suspended at 25 ° C in 500 ml of 1-methoxy-2-propanol. Under nitrogen was heated to 80 ° C, resulting in a homogeneous solution. It was then cooled to 40 ° C and 7.8 g (0.0476 mol) of 2,7-dimethyl-2,4,6-octatriene-1,8-dial (99 wt .-%, all-E / 4Z = 2/1) was added. After stirring for 30 minutes at 40 ° C, the solution was cooled to about 25 ° C and added dropwise within 10 minutes 20 g (0.11 mol) of a 30% sodium methylate solution. Subsequently, the reaction mixture was stirred at 30 ° C for 2 hours.

After addition of 2 ml of glacial acetic acid, the reaction mixture was heated to 100 ° C and stirred at this temperature for 4 hours. After cooling to room temperature (23 ° C), the precipitated astaxanthin was filtered off, washed with about 800 ml of 40 ° C warm methanol and 400 ml of 70 ° C warm water and dried at 50 ° C in a drying oven under inert gas.
Yield: 20 g (70.57% of theory) purity 97% (determined by HPLC).

Example 3

60 g (0.104 mol) of 3-methyl- (2,6,6-timethyl-3-oxo-4-hydroxy-1-cyclohexen-1-yl) -2,4-pentadienyl-triphenylphosphonium bromide (asta-C ₁₅ -triphenylphosphonium bromide ) were suspended under nitrogen at 25 ° C in 200 ml of diethylene glycol monomethyl ether. It was heated to 80 ° C, resulting in a homogeneous solution. It was then cooled to 40 ° C and 7.8 g (0.0476 mol) of 2,7-dimethyl-2,4,6-octatriene-1,8-dial (99 wt .-%, all-E / 4Z = 2/1) was added. After stirring for 30 minutes at 40 ° C, the solution was cooled to about 25 ° C and added dropwise within 30 minutes 20 g of a 30% sodium methylate solution. Subsequently, the reaction mixture was stirred at 30 ° C for 2 hours.

Thereafter, the reaction mixture was heated to 100 ° C and stirred at this temperature for 4 hours. After cooling to room temperature (23 ° C), the precipitated astaxanthin was filtered off, washed with about 800 ml of 40 ° C warm methanol and 400 ml of 70 ° C warm water and dried at 50 ° C in a drying oven under inert gas.
Yield: 21.3 g (75.2% of theory) purity 96% (determined by HPLC).

Example 4

60 g (0.104 mol) of 3-methyl- (2,6,6-trimethyl-3-oxo-4-hydroxy-1-cyclohexen-1-yl) -2,4-pentadienyl-triphenylphosphonium bromide (Asta-C ₁₅ -triphenylphosphonium bromide ) and 7.8 g (0.0476 mol) of 2,7-dimethyl-2,4,6-octatriene-1,8-dial (99% by weight; all-E / 4Z = 2/1) were dissolved in 180.degree ml of methylene chloride at room temperature (21 ° C) and then treated with 180 ml of diethylene glycol monomethyl ether (methyl diglycol). The solution was cooled to 0 to 3 ° C and treated at the temperature within 1 hour with 6 g (0.11 mol) of sodium in 24 g of methanol. After 1.5 hours, 2 ml of glacial acetic acid were added and the mixture was heated slowly to 105-107 ° C. In this case, methylene chloride / methanol was distilled off. After reaching the Isomerisierungstemperatur was stirred for 4 hours. Then allowed to cool to room temperature (24 ° C), filtered through a G3 glass frit and washed the filter residue with: 200 ml of methanol (50 ° C), 300 ml of deionized water (about 80 ° C) and then again with 200 ml of methanol (40 ° C). Was dried at 50 ° C under inert gas.
Yield: 23.8 g (84% of theory); Purity: 97.7% (determined by HPLC).

Claims (4)

Process for the preparation of astaxanthin of the formula I

by reacting 2 mol of the triphenylphosphonium salt of the general formula II

in which X is chlorine, bromine or (HS04) ^- radical is, in a Wittig reaction with one mole of C ₁₀ -Dialdehyds of formula III

characterized in that A. the starting compounds of the formulas II and III in one or more solvents selected from the group consisting of ethylene glycol monomethyl ether, 1-methoxy-2-propanol and compounds of general formula IV R ^{1 is} -O- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OR ² IV, in which the substituents independently of one another have the following meaning: R ^{1 is} hydrogen, C ₁ -C ₄ -alkyl; R ² C ₁ -C ₄ alkyl, C (= O) -C ₁ -C ₄ alkyl suspended, the suspension is heated to temperatures of 30 to 90 ° C until a homogeneous solution has formed, B. the resulting homogeneous solution at temperatures of 0 to 40 ° C with 1 to 1.2 moles per mole of triphenylphosphonium salt of a usual base for Wittig reactions added and C. the precipitated in step B. astaxanthin at temperatures of 90 to 130 ° C under atmospheric pressure in one or more the isomerized under A. solvents and then isolated. Process according to Claim 1, characterized in that a solvent selected from the group consisting of ethylene glycol monomethyl ether, 1-methoxy-2-propanol and methyl diglycol of the formula CH ₃ O- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ - OH used. Method according to one of claims 1 or 2, characterized in that reacting a triphenylphosphonium salt of the general formula II, in which X is bromine, with the C ₁₀ -dialdehyde of the formula III. Method according to one of claims 1 to 3, characterized that in the reaction step B, the homogeneous solution of the starting compounds with an aqueous solution of sodium hydroxide or potassium hydroxide, a methanolic solution of sodium methoxide or an ethanolic sodium ethoxide solution.