DE4430289A1 - Improved process for the preparation of astaxanthine - Google Patents

Abstract

Process for preparing astaxanthine by reacting A. The tertiary alcohol of the formula II or the diacetate of the formula III <IMAGE> with aqueous hydrobromic acid or hydrochloric acid in an inert solvent, B. Reacting the resulting halide of the formula IV <IMAGE> with triphenylphosphine in an inert solvent and C. Reacting the resulting triphenylphosphonium salt with 2,7-dimethyl-2,4,6-octatriene-1,8-dial in a Wittig reaction, which is characterised in that, in reaction step B, the halide of the formula IV is reacted with the triphenylphospine in an open-chain lower-dialkyl ether, triphenylphosphonium salt of the formula V being obtained in a form in which it can be readily filtered, and this is reacted in reaction step C in a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial while simultaneously or subsequently eliminating the acetyl groups, or else in that, in reaction step A, the starting compound of the formula II or III is reacted with aqueous hydrobromic acid or hydrochloric acid in methylene chloride, the resulting solution of the halide of the formula IV is reacted with triphenylphosphine, and the resulting solution of the triphenylphosphonium salt of the formula V is reacted with 2,7-dimethyl-2,4,6-octatriene-1,8-dial in a Wittig reaction in methylene chloride while eliminating the acetyl groups.

Description

The invention relates to an improved process for the preparation of the C₄₀ carotenoid astaxanthin of the formula I.

and the production of an essential precursor, the tri phenylphosphonium salt of the formula V

in which X is Br (a) or Cl (b), in crystalline form.

Astaxanthin is a coveted color for fish pigmentation material. A technically feasible manufacturing process for Asta xanthine is based on the synthesis principle C₁₅ + C₁₀ + C₁₅ = C₄₀ (see. EP 5748 and Helv. Chim. Acta 64 (1981), pages 2436-2446)).

As C₁₅-building block is the triphenylphosphonium 1 used. It is used in a double Wittig condensation with 2,7-dimethyl-octa-2,4,6-triene-1,8-dial 2 to astaxanthin implemented.

As starting material for the C₁₅-phosphonium salt 1 is under the tertiary alcohol 3-acetoxy-4-oxo-9-vinyl-β-ionol of Formula II described.

(see EP 5749), which in a multi-stage reaction sequence from the industrially available β-ionone is accessible. Like that Executions in Helv. Chim. Acta 64 (1981), pages 2419-2435, especially page 2422, has been found in attempts to from the tertiary alcohol of the formula II in per se known Example, the corresponding Triphenylphosphoniumsalz the formula

Produce this only in the form of an extremely poor crystalline obtained in the Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial with saponification only be  yielded a fraction of astaxanthin. Because of this unbe Satisfying results, these experiments were not further works, but the tertiary alcohol of formula II under strict oxygen exclusion at 0 ° C to give the corresponding dihydroxy Saponified compound and then this for the production of Asta xanthine used (see EP 5749).

Given this state of the art, it was not expected that one could find process conditions that make it possible the acetylated triphenylphosphonium salt of the formula V in to obtain good yields and in a well-crystallized form. Furthermore, it was not to be expected that in the next stage Wittig reaction with the C₁₀-dialdehyde with saponification or Transesterification of the acetoxy group astaxanthin in high yields could receive. Such a possibility would be out of ver drive technical and economic point of view advantageous because the Synthesis of astaxanthin directly from 3-acetoxy-4-oxo-9-vinyl β-ionol would thereby shortened by one step.

It was therefore the object of the invention, the production of Asta xanthine from 3-acetoxy-4-oxo-9-vinyl-β-ionol or another to improve the readily available 6-acetoxy-cyclohexanone so that the complex hydrolysis to the corresponding 6-hydroxy compound can be omitted.

The invention relates to a process for the preparation of Astaxanthin of the formula I

by reacting

• A. of the tertiary alcohol of the formula II or of the diacetate of the formula III in an inert solvent with aqueous hydrobromic acid or hydrochloric acid,
• B. Reaction of the resulting halide of formula IV in which X is Br (a) or Cl (b), in an inert solvent with triphenylphosphine
  and
• C. Reacting from about 2 to 3 moles of the resulting triphenyl phosphonium salt of the formula V where X is Br (a) or Cl (b),
  with 1 mole of 2,7-dimethyl-2,4,6-octatriene-1,8-dial, in a Wittig reaction, which is characterized in that in the reac tion stage B, the halide of the formula IV with the triphenyl phosphine in an open-chain dialkyl ether of the general formula VIR 1 -O-R 2 VI in which R 1 is an alkyl radical having 1 to 4 C atoms and R 2 is an alkyl radical having 2 to 4 C atoms,
  as the inert solvent, wherein the Triphenylphos phoniumsalz of formula V is obtained in readily filterable form and this in reaction step C.
  reacted in a Wittig reaction with simultaneous or subsequent cleavage of the acetyl groups with 2,7-dimethyl-2,4,6-octatriene-1,8-dial
  or that one
  in reaction step A, the tertiary alcohol of the formula II or the diacetate of the formula III in methylene chloride with aqueous bromine or hydrochloric acid and reacts after aqueous processing and separation of water in reaction step B, the resulting solution of the halide of formula IV in methylene chloride with triphenylphosphine and in reaction stage C, the resulting solution of Triphenylphosphoniumsalzes of formula V in methylene chloride after cooling to temperatures of -5 to + 25 ° C in a Wittig reaction with simultaneous or subsequent cleavage of the acetyl groups with 2,7-dimethyl-2,4 , 6-octa-trien-1,8-dial.

In the process of the invention, the be obtained belonged to astaxanthin in excellent yields.

This was very surprising, as it is also in DE 26 53 838 for the Reaction of acylated in the 6-position C₁₅-triphenylphosphonium Salting with 2,7-dimethyl-2,6-octadiene-4-in-1,8-dial means that only the acyloxy substituted by halogen, alkoxy or aryloxy groups in the present system of the Wittig reaction to hydroxy group can be saponified without this in the saponification partially converted to the oxo group.

That the triphenylphosphonium salt of the formula V in good crystallizable form was surprising since it was in Helv. Chim. Acta 64 (1981), pages 2405 to 2418, in particular Page 2409, means that the corresponding Triphenylphos phonium salt with an unprotected hydroxyl group in the 6-position in contrast to the otherwise preferred ones with a phenoxyacetyl group in the 6-position protected Triphenylphosphoniumsalz out draws crystallize.

According to the invention, the procedure is that in the Wittig reaction the reaction step C, the deprotonation of triphenylphosphonium salts of formula V with simultaneous elimination of acetyl group with the solution of an alkali metal hydroxide in a low ren primary alkanol, with a concentrated aqueous solution  an alkali metal hydroxide optionally in combination with a Water-miscible alkanol as a solubilizer or with the solution of an alkali metal alkoxide of a lower primary Alkanols performs in this alkanol, or first the Wittig reaction with the C₁₀-dialdehyde and then from the resulting mixture of astaxanthin bis-acetate and Astaxanthin monoacetate acetyl groups by saponification or Transesterification splits off.

The as starting compound for the process according to the invention used tertiary alcohol of formula II, the 6-acetoxy-2,4,4- trimethyl-3- (3-hydroxy-3-methyl-penta-1,4-dien-1-yl) -2-cyclo Hexene-1-one is in the prior art in a multi-stage reaction produced from the industrially available β-ionone (See Helv. Chim. Acta 64 (1981), pages 2419-2435).

The diacetate of the formula III used as the starting compound, the 6-acetoxy-2,4,4-trimethyl-3- (5-acetoxy-3-methyl-1,3-penta dien-1-yl) -2-cyclohexen-1-one, may be prepared from the diol of the formula

its production in Helv. Chim. Acta 65 (1982), pages 671-683, is described, for example, by reducing the triple binding with zinc powder / acetic acid, allyl rearrangement with acetic acid in the presence of catalytic amounts of para-toluenesulfonic acid and Acetylation of the secondary hydroxy group with acetic anhydride to hold.

The starting compounds II or III are in reaction step A dissolved in an inert organic solvent and by Um with aqueous HBr or HCl into the halides of the formula IV transferred. As a solvent, for example, toluene or Methylene chloride into consideration. With special advantage one works in methylene chloride.

The hydrohalic acid is generally used in the form of concentrated aqueous solutions in amounts of 1 to 5 equi valenten, based on the starting compounds II or III.  

The reaction temperatures are generally 0 ° C. to Boiling temperature of the solvent, preferably 25 to 40 ° C, the required reaction times depend on the temperature and on the Amount of used hydrohalic acid from. They amount z. When using 3 equivalents of HBr at room temperature about 15 to 24 hours, preferably 18 to 22 hours.

For working up the reaction mixture, dilute with water, separates the organic phase and washed acid-free, which z. B. can be done with dilute NaHCO₃ solution.

The implementation of the reaction stage B can in various ways be advantageous.

For the preparation of well-crystallized Triphenylphosphoniumsalz the formula V leads to the reaction with triphenylphosphine in an open-chain dialkyl ether.

Examples of suitable lower dialkyl ethers are:
Diethyl ether, di-n-butyl ether and preferably methyl tert-butyl ether and diisopropyl ether. For this variant of the reaction with triphenylphosphine (TPP), a solvent exchange must be carried out at the stage of the halide of the formula IV. This can be done by evaporating the solution of the halide and dissolving the residue in the dialkyl ether. Preferably, however, the reaction stage is carried out in methylene chloride and distilled off this with simultaneous feed of a chloride methyl chloride boiling higher than methylene. When distilling off the solvent, it is advisable to add to the reaction mixture, some 1,2-epoxybutane for capturing excess hydrogen halide acid. The resulting ethereal solution of the halide is then reacted with TPP in the form of an ethereal solution, preferably a solution in the same dialkyl ether or else with solid TPP.

TPP is generally used in amounts of from 0.8 to 2 equivalents valenten, preferably 1 to 1.5 equivalents, based on the Starting compounds II and III. Expediently, the solution is dripped of the halide to the solution of TPP in the temperature range of 0 ° C to room temperature. The solution of TPP can be seed crystals of the triphenylphosphonium salt of the formula V are added. The Crystallization also succeeds without the use of Impfkri are good. The suspension of Triphenylphosphoniumsalzes is generally after 4 to 20, preferably about 6 hours Nach stir and filter cake with the appropriate solution washed and dried medium.  

It was also surprisingly found that one also then obtain very good yields of pure astaxanthin, if you do not pass through the triphenylphosphonium salt of the formula V. Crystallization isolated, but in solution with the dialdehyde condensed to astaxanthin. According to the prior art will in general, the triphenyl used for the final stage Phosphonium salt basically crystallizes to it by addition to clean the products of the synthesis.

The waiver of the isolation of Triphenylphosphoniumsalzes makes the solvent exchange before crystallization, connected with the distillative reprocessing required hereby of mixed solvent fractions, as well as the technically complex Solid-state handling (filtration, drying, discharging, storage, Redissolving) superfluous. In detail, this is Process variant proceeded as follows:

A solution of a halide obtained in reaction step A. of formula IV is after aqueous workup and removal of the Water is treated with TPP as a solid or as a solution, and the reaction mixture in the temperature range of about 0 to 40 ° C, preferably at room temperature, still 2 to 20, preferably 2 to 6 hours stirring. For this variant of the invention According to the method used with advantage methylene chloride as Solvent. The solution of triphenylphosphonium thus obtained salts in methylene chloride can then be added directly to the Wittig Reak tion (reaction stage C) can be used.

For the preparation of astaxanthin according to reaction step C is a Solution of Triphenylphosphoniumsalzes of formula V with the symme trivalent dialdehyde 2,7-dimethyl-2,4,6-octatriene-1,8-dial in one Wittig reaction preferably under reaction conditions which also leads to the elimination of the acetyl groups. The Reaction is carried out in an inert solvent. Out Löslichkeitsgründen is methylene chloride as a solvent before Trains t.

Deprotonation of the triphenylphosphonium salt becomes bases which also uses the acetyl groups by saponification or remove by transesterification. To saponify the acetyl groups to cleave as the base, the solution of an alkali metal hydroxide optionally in a lower primary alkanol, preferably methanol or ethanol, or the concentrated aqueous solution of the alkali Metallhydroxids possibly in combination with a lower primary Alkanol used as a solubilizer. If you renounce the Using a solvent and working in two phases, then you get the astaxanthin-bis-acetate, which subsequently  could be saponified to astaxanthin. A preferred off example, the use of a 10 bis 25 wt .-% solution of solid potassium hydroxide in methanol. Basically, per equivalent of triphenylphosphonium salts at least 2 equivalents, preferably 2.05 to 2.5 eq valente of the base used. The reaction temperature is in Range from -10 ° C to room temperature, preferably at about 0 ° C.

For deprotonation of Triphenylphosphoniumsalzes under Abspal tion of the acetyl groups by transesterification becomes the base as the solution an alkali metal alkoxide of a lower primary alkanol in the corresponding alkanol, preferably methanolic sodium methylate solution or ethanolic Natriumethylatlösung in Kon concentration range of about 10 to 30 wt .-% used. Pro equi valent triphenylphosphonium salt are about 1.05 to 2.5 eq valent base used. The reaction temperature is also preferably at -10 ° C to room temperature, preferably at about 0 ° C.

But it is also possible that in the reaction step C first the triphenylphosphonium salt of formula V in a Wittig reaction tion with 2,7-dimethyl-2,4,6-octatriene-1,8-dial to astaxanthin bis-acetate or a mixture of astaxanthin-bis-acetate and Astaxanthin monoacetate converts and from these then only the Acetyl groups by saponification or transesterification with the above splits off bases described.

To carry out the Wittig reaction is used in this case only about 1 to 1.25 moles of one for Wittig reactions usually used base. Usually used for Wittig reactions dete bases come in addition to the above alkali metal hydroxides and Alkali alkoxides also weaker bases, such as ammonia and epoxides, in particular 1,2-epoxy-butane into consideration.

The astaxanthin obtained in the reaction according to the invention is a mixture of isomers consisting essentially of all-E-Asta xanthine, 11-cis-astaxanthin and 11,11'-di-cis-astaxanthin.

It can in a conventional manner thermally into the desired all-e-astaxanthin are converted.

Astaxanthin can also be used with the aid of the method according to the invention starting from the 6-acetoxy-substituted starting compounds II or III advantageously in good yields and in good purities are produced.

example 1 A. Preparation of the bromide of formula IVa

44 g of the tertiary alcohol (3-acetoxy-4-oxo-9-vinyl-β-ionol) of the formula II (purity about 80%, 12 mol) were in 200 ml of methylene chloride dissolved. This solution was dripped into 15 minutes (min) with cooling in an ice-water bath (reaction temperature about + 5 ° C) to 40 g of a 47% aqueous HBr. The mixture was stirred for 30 min in an ice water bath and then left 150 ml Run in water. The organic phase (below) was abge separates and the water phase with 40 ml of methylene chloride after extracted. The combined organic phases were each one with 150 ml of a 5% sodium bicarbonate solution and 150 ml of water. After addition of 1.5 ml 1,2-epoxybutane as a scavenger of excess HBr distilled at atmospheric pressure, methylene chloride under simultaneous Inlet of methyl tert-butyl ether (MTB) from until over going distillate had reached a temperature of + 55 ° C. The sump volume was kon in this solvent exchange kept constant.

B. Preparation of Triphenylphosphonium Bromide of Formula Va

The obtained from Example 1A solution of 6-acetoxy-2,4,4- trimethyl-3- (5-bromo-3-methyl-1,3-pentadiene-1-yl) -2-cyclo hexene-1-one (bromide of formula IVa) in MTB was subsequently added within 1 hour (h) at room temperature (RT) to a Solution of 39 g of triphenylphosphine (TPP) in 200 ml of MTB, the 900 mg of crystalline triphenylphosphonium bromide of the formula V were added to the inoculation, dripped. It was stirred for about 6 h at RT and filtered off. The filter cake was made with MTB washed and dried in a stream of nitrogen.

Weighing | 70.0 g Purity according to potentiometric titration on bromide about 85% yield 0.096 mol corresponding to 80.4% of theory (ie Th.)

C. Preparation of astaxanthin from crystalline triphenylphosphine Phonium bromide of the formula Va with saponification of acetyl groups

In a 1 liter stirred reactor, 210 ml of methylene chloride submitted, cooled to -10 ° C and with 61 g (84 mmol) of the according to Example 1B prepared Triphenylphosphoniumbromids the  Formula Va (salary 85%) added. The temperature rose at 0 ° C. To this solution was added 5.16 g (31.5 mmol) 2,7-dimethyl-octa-2,4,6-triene-1,8-dial (C₁₀-dialdehyde). inner half of 2 h was added dropwise at 0 ° C under inert gas atmosphere a solution of 12.48 g (0.189 mol) of potassium hydroxide in 120 ml Methanol too. Then the reaction mixture was allowed to stand at 0 ° C for 1 h afterreact. After addition of 6 g (0.1 mol) of glacial acetic acid and 225 ml of water was stirred for 5 min and then separated the Phases. The water phase (pH 5) was mixed with 30 ml of methylene washed chloride. The combined methylene chloride phases washed with 100 ml of water.

D. Isomerization to All-E-Astaxanthin

The methylene chloride phases of two in the above described Were carried out approaches in the stirred reactor verei nigt; the solvent was passed through a 20 cm packed body column replaced with methanol (600 ml). Than that distilling solvent a temperature of 65 ° C he was enough, closed the reactor, heated the contents for thermal isomerization 8 h at 75 ° C (1.5 bar) and isolated the desired product after cooling to 0 ° C by Ab filter under inert gas.

The filter cake was washed with 40 ml of methanol at 0 ° C and taken up in 510 ml of methylene chloride. The solvent Replacement with methanol (600 ml) was described in the above repeated manner. Then it was heated under own pressure 8 h at 95 ° C, cooled to 0 ° C and isolated all-E-Asta xanthine by suction under inert gas. The value product became washed with 40 ml of methanol from 0 ° C and at + 50 ° C under ver dried under reduced pressure.

Weighing | 28.36 g yield 75.4% d. Th. Content according to UV 98.4% Content of semi-astacin by HPLC 1.8%

Example 2 Preparation of astaxanthin from crystalline triphenylphosphine phonium bromide of the formula Va with transesterification of the acetyl groups

In a 1 liter stirred reactor, 210 ml of dichloromethane were added cooled, cooled to -10 ° C and with 61 g (84 mmol) of an analogous play 1A and 1B produced Triphenylphosphoniumbromids the Formula Va (salary 85%) added. The temperature rose  0 ° C on. To this solution was added 5.16 g (31.5 mmol) of 2,7-dimethyl octa-2,4,6-triene-1,8-dial. Within 2 h, it was dropped at 0 ° C under inert gas atmosphere a solution of 10.77 g (199 mmol) Sodium methylate in 120 ml of methanol. The mixture was allowed to stir at 0 ° C. for 1 h react, then put 9 g (0.15 mol) of glacial acetic acid and 225 ml of water to and worked analogously to Example 1C.

The methylene chloride phases of two in the above described Ways were made as in Example 1D combined and exchanged the methylene chloride for methanol.

Subsequently, the reactor contents were kept at thermal Isomerization of the resulting astaxanthin for 16 h at reflux temperature and isolated the desired product after cooling to 0 ° C. by filtering under inert gas.

The methanol-moist primary crystals were as in Example 1 be written in methylene chloride and dissolved by solvent exchange transferred into a methanolic suspension. It was heated 8 h Reflux temperature, cooled to 0 ° C and isolated all-E-Asta xanthine by filtration under inert gas. The value product became washed with 40 ml of methanol from 0 ° C and then at + 50 ° C under ver dried under reduced pressure.

Weighing | 30.32 g yield 80.6% d. Th. Content according to UV 98.7% Content of semi-astacin by HPLC 2.7%

Example 3 Production of astaxanthin without isolation of triphenylphosphine phonium bromides of the formula Va A. Preparation of the bromide of formula IVa

44 g of the tertiary alcohol of the formula II (purity about 80%;  0.12 mol) were prepared as described in Example 1A Methylene chloride by reaction with a 47% aqueous HBr converted into the bromide of formula IVa. After the aqueous Work-up was added 1.5 ml of epoxybutane for trapping HBr and dried the methylene chloride solution by circling out water.  

B. Preparation of Triphenylphosphonium Bromide of Formula Va

To the solution obtained according to Example 3A was added 31.5 g (0.12 mol) of TPP and stirred for 17 h at RT.

C. Preparation of astaxanthin

Subsequently, the resulting solution of triphenyl was cooled phosphonium bromide of formula Va to 0 ° C and added 5.9 g (0.036 mol) of 2,7-dimethyl-octa-2,4,6-triene-1,8-dial. Within 2 h was added dropwise at 0 ° C under inert gas Atmosphere a solution of 12.36 g (0.22 mol) of potassium hydroxide in 120 ml of methanol. Then it was stirred for 1 h at 0 ° C, gave 13.2 g (0.22 mol) of glacial acetic acid and 250 ml of water were added and stirred 5 min after. The phases were separated. The water phase was with 50 ml of methylene chloride nachextrahiert. The United organic phases were washed with 150 ml of water.

D. Isomerization to All-E-Astaxanthin

At atmospheric pressure methylene chloride was added under simultaneous Distilled off the feed of methanol. As the distilling off Solvent had reached a temperature of + 65 ° C was the suspension for thermal isomerization for 16 h under Refluxing stirred. The product was cooled filtered off at 0 ° C under inert gas and twice with 50 ml Methanol at 0 ° C and once with 50 ml of heptane at 0 ° C washed. The Erstkristallisat was with methylene chloride taken and by solvent exchange in a metha transferred nolische suspension. The mixture was heated under reflux for 16 h boiled, then cooled to 0 ° C and isolated all E-Astaxanthin by filtering under inert gas. The filter cake was washed twice with 50 ml of methanol at 0 ° C and once washed with 50 ml of heptane of 0 ° C and in a stream of nitrogen dried.

Weighing | 16.31 g yield 76.0% Content according to UV 98.4% Content of semi-astacin by HPLC 2.8%

Example 4 Making astaxanthin-bis-acetate

• A. In a 4-liter stirred reactor, 1000 ml of methylene chloride were introduced, cooled to -10 ° C and treated with 350 g of Triphenylphosphoniumbromids prepared according to Example 1B (85%, 0.482 mol) of the formula Va. The temperature rose to 0 ° C. To this solution was added 24.6 g (0.15 mol) of 2,7-dimethyl-2,4,6-octatriene-18-dial. Within 2 h was allowed to run at 0 ° C, a solution of 25.2 g (0.45 mol) of KOH in 250 ml of methanol. The mixture was stirred for 1 h at 0 ° C, 27 g (0.45 mol) of acetic acid and 2 l of water, warmed to RT and the organic phase was separated. The water phase was extracted twice with 50 ml of methylene chloride each time. The combined organic phases were washed once with 2 l of water. The methylene chloride was distilled off at normal pressure with simultaneous feed of methanol until the temperature of the solvent distilling off was 65 ° C. The suspension was stirred for 18 h under reflux. It was cooled to 0 ° C and filtered off. The filter cake was washed with cold (0 ° C) methanol and taken up in 1 liter of methylene chloride. The solvent exchange against methanol was repeated in the manner described above. The mixture was heated again under reflux for 18 h and isolated the Wertpro product by filtration at 0 ° C. It was washed with cold (0 ° C) methanol and dried in N₂ stream. Weighing | 63.4 g yield 62.2% d. Th. HPLC analysis 93.5% astaxanthin-bis-acetate 5.6% astaxanthin mono-acetate
• B. 22 g of the triphenyl phosphonium bromide prepared according to Example 1B of the formula Va (85%, 30.3 mmol) and 1.9 g (11.6 mmol) of 2,7-dimethyl-2,4,6-octatriene-1 8-dial was refluxed in 100 ml of butylene oxide for 5 hours. Then the batch was concentrated on a rotary evaporator. The residue was purified by flash chromatography on silica gel (eluent: methylene chloride: diethyl ether = 9: 1). The astaxanthin bis-acetate fraction was taken up with 40 ml of methanol and heated for 18 h under reflux to boiling it. It was cooled to 0 ° C, filtered off, washed with cold methanol and dried in N₂ stream. Final weight 5.9 g of H-NMR-pure astaxanthin bis-acetate yield 74.8% d. Th.

Example 5 Production of astaxanthin with Wittig reaction in butylene oxide and subsequent cleavage of the acetyl groups

86 g of the triphenylphosphonium prepared according to Example 1B bromides of the formula Va (85%, 118.5 mmol) and 7.8 g (47.56 mmol) of the C₁₀-dialdehyde 2,7-dimethyl-2,4,6-octatriene 1,8-dial were dissolved in 250 ml of butylene oxide (1,2-epoxybutane) for 18 h heated to boiling under reflux. Then the solvent became withdrawn on a rotary evaporator. The residue was dissolved in 660 ml Dissolved methylene chloride. At 0 ° C was added dropwise 146 ml of a 10% methanolic KOH solution and stirred for 1 h at 0 ° C after. Then the batch was poured onto water, the water phase separated and once extracted with methylene chloride. The United organic phases were washed twice with water and under Normal pressure the methylene chloride under simultaneous feed from Distilled off methanol until the solvent distilling off had reached a temperature of + 65 ° C. The suspension was Stirred for 18 h while heating to reflux. After that cooled to 0 ° C and filtered off. The filter cake was with washed cold (0 ° C) methanol and with 400 ml of methylene chloride added. The solvent exchange against methanol was in the repeated manner. It was heated again for 18 h Heat to reflux and isolated the desired product Filter off at 0 ° C, wash with cold (0 ° C) methanol and Drying in N₂ stream.

Final weight 21.3 g astaxanthin yield 75.1% d. Th.

Claims (9)

1. A process for the preparation of astaxanthin of the formula I. by reacting

• A. of the tertiary alcohol of the formula II or of the diacetate of the formula III in an inert solvent with aqueous hydrobromic or hydrochloric acid,
• B. Reaction of the resulting halide of formula IV in which X is Br (a) or Cl (b), in an inert solvent with triphenylphosphine
  and
• C. Reacting 2 to 3 moles of the resulting triphenyl phosphonium salt of the formula V where X is Br or Cl,
  with 1 mole of 2,7-dimethyl-2,4,6-octatriene-1,8-dial, in a Wittig reaction, characterized in that in the reac tion stage B, the halide of formula IV with the triphenyl phosphine in a open-chain dialkyl ethers of the general formula VIR 1 -O-R 2 VI in which R 1 is an alkyl radical having 1 to 4 C atoms and R 2 is an alkyl radical having 2 to 4 C atoms,
  as the inert solvent, wherein the Triphenylphos phoniumsalz of formula V is obtained in readily filterable form, and this in reaction step C.
  reacted in a Wittig reaction with simultaneous or subsequent cleavage of the acetyl groups with 2,7-dimethyl-2,4,6-octatriene-1,8-dial
  or that one
  in reaction stage A, the tertiary alcohol of formula II or the diacetate of formula III in methylene chloride with aqueous hydrobromic acid or hydrochloric acid and after aqueous workup and separation of water in reac tion stage B, the resulting solution of the halide of formula IV in methylene chloride with triphenylphosphine and in reaction step C, the resulting solution of tri phenylphosphoniumsalzes of formula V in methylene chloride after cooling to temperatures of about 5 to + 25 ° C in a Wittig reaction with simultaneous or subsequent cleavage of the acetyl groups with 2,7-dimethyl-2,4 , 6-octa-trien-1,8-dial.

2. The method according to claim 1, characterized in that one in the Wittig reaction of reaction stage C the Deproto nisierung of Triphenylphosphoniumsalzes of formula V below simultaneous elimination of the acetyl groups with the solution an alkali metal hydroxide in a lower primary Alkanol or with a concentrated aqueous solution of a Alkalimetallhydroxids optionally in combination with a Water-miscible alkanol performs as a solubilizer. 3. The method according to claim 1, characterized in that one in the Wittig reaction of reaction stage C the Deproto nisierung of Triphenylphosphoniumsalzes of formula V below simultaneous elimination of the acetyl group with the solution an alkali metal alkoxide of a lower primary alkanol in this alkanol performs. 4. The method according to claim 3, characterized in that one in the Wittig reaction of reaction stage C the Deproto nisierung of Triphenylphosphoniumsalzes of formula V below simultaneous removal of the acetyl groups with metha nolic sodium methylate solution or with ethanolic Sodium ethylate solution is carried out. 5. The method according to claim 1, characterized in that one in reaction stage C, first the Wittig reaction of Triphenylphosphonium salt with 2,7-dimethyl-2,4,6-octatriene-1,8-dial and then from the obtained Astaxanthin-bis-acetate or the mixture obtained from Astaxanthin monoacetate and astaxanthin-bis-acetate acetyl cleavage groups by saponification or transesterification. 6. The method according to claim 1, characterized in that one in the reaction step A, the tertiary alcohol of the formula II or the diacetate of formula III in methylene chloride as inert solvent with hydrochloric acid or bromine reacted hydrogenic acid and after a solvent exchange in reaction stage B, the resulting halide of formula IV in an open-chain dialkyl ether as a solvent with Reacting triphenylphosphine, the resulting triphenyl crystallized phosphonium salt of the formula V and in Reaction step C the isolated Triphenylphosphoniumsalz of formula V with elimination of the acetyl groups with 2,7-dimethyl-2,4,6-octatriene-1,8-dial.   7. A process for the preparation of crystalline 5- (4-acetoxy-3-oxo-2,6,6-trimethylcyclohex-1-enyl) -3-methyl-penta-2,4-diene-1-triphenylphosphonium bromide or chloride the formula V where X is Br or Cl,
by reacting

• A. of the tertiary alcohol of the formula II or of the diacetate of the formula III with aqueous hydrobromic acid or hydrochloric acid in an inert solvent and
• B. Reaction of the resulting halide of formula IV with triphenylphosphine in an inert solvent, characterized in that the reaction step B in an open-chain dialkyl ether of the formula VIR¹-O-R² VI in the R¹ and R² is an alkyl radical having 2 to 4 carbon atoms, carried out, wherein the triphenylphosphonium the Formula V is obtained in easily filterable form.

8. The method according to claim 1, characterized in that one in reaction stage B, the ethereal solution of the halide of formula IV at temperatures of 0 to 25 ° C to a added ethereal solution of triphenylphosphine. 9. The method according to claim 1, characterized in that one at temperatures from 0 to 25 ° C solid triphenylphosphine too of the ethereal solution of the formula IV halide.