METHOD FOR PRODUCING ASTAXANTHIN ESTERS

Abstract

The invention describes an environmentally friendly, sustainable and cost-effective method for preparing astaxanthin diesters of the formula 1, in which astaxanthin of the formula 2 is doubly esterified with fatty acid chlorides of the general formula 3. For this purpose, compound 2 and 3 are reacted in an organic solvent in the presence of a nitrogen-containing base of the general formula 4. The invention further relates to the non-therapeutic use of the diester 1, in which R is a residue selected from the group consisting of C13-C19-alkyl, C13-C19-alkenyl, C13-C19-alkdienyl and C13-C19-alktrienyl, in human or animal nutrition and also the therapeutic use of the diester 1 prepared according to the method as a medicament and also as an ingredient in a medicinal preparation.

Claims

1. A method for preparing an astaxanthin diester of formula (1) ##STR00007## in which the asymmetric center in position 3 and 3′ is racemic, or each has (S) or (R) configuration and R is a residue selected from the group consisting of C9-C19-alkyl, C9-C19-alkenyl, C9-C19-alkdienyl and C9-C19-alktrienyl, wherein astaxanthin of formula (2) ##STR00008## in an organic solvent is reacted with an acid chloride of formula (3) ##STR00009## in which R is as defined in formula (1), in the presence of at least one nitrogen-containing base of formula (4) to provide a reaction product mixture
NR.sup.1R.sup.2R.sup.3  (4) in which R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of a saturated C1-C6 chain, an unsaturated C1-C6 chain, an aromatic C6 ring, a C1-C6 chain formed from two of the three residues R.sup.1, R.sup.2 and R.sup.3, wherein said two residues are linked to each other and, together with the nitrogen atom of the base (4), form an alkylated or non-alkylated heterocycle or an alkylated or non-alkylated heteroaromatic cycle, or a C1-C6 chain formed from two of the three residues R.sup.1, R.sup.2 and R.sup.3, wherein said two residues are linked to each other via a further nitrogen atom and, together with the nitrogen atom of the base (4), form an alkylated or non-alkylated heterocycle or an alkylated or non-alkylated heteroaromatic cycle.

2. The method according to claim 1, wherein the astaxanthin of the formula (2) in the organic solvent is reacted with a greater than two-fold molar excess, based on astaxanthin (2), of the acid chloride of the formula (3) in the presence of at least one nitrogen-containing base of the formula (4).

3. The method according to claim 1, wherein the astaxanthin of the formula (2) in the organic solvent is reacted with a 2.3-fold to 7-fold molar excess, of the acid chloride of the formula (3) in the presence of at least one nitrogen-containing base of the formula (4).

4. The method according to claim 1, wherein the organic solvent is a chlorine-containing organic solvent selected from the group consisting of dichloromethane, trichloromethane, tetrachloromethane, 1,1-dichloroethane, 1,2-dichloroethane, trichloroethylene, tetrachloroethylene, perchloroethylene, chlorobenzene or a mixture of at least two of the chlorine-containing organic solvents.

5. The method according to claim 4, wherein the astaxanthin of the formula (2) in the organic solvent is reacted with the acid chloride of the formula (3) at a temperature range of −20 to +100° C.

6. The method according to claim 1, wherein the at least one nitrogen-containing base of the formula (4) is selected from the group consisting of monocyclic nitrogen-containing bases, and bicyclic nitrogen-containing bases.

7. The method according to claim 1, wherein the present in a 1.1 to 2-fold molar ratio, based on the acid chloride.

8. The method according to claim 1, wherein the reaction product mixture is treated with at least one compound selected from the group consisting of alcohols of the formula (5)
R.sup.4OH  (5) where R.sup.4 is equal to C1-C6-alkyl; and amines of the formula (6)
R.sup.5R.sup.6NH  (6) where R.sup.5 and R.sup.6 are each independently equal to H or C1-C6-alkyl, in which R.sup.5 and R.sup.6 either each form an independent group or are linked to each other.

9. The method according to claim 8, wherein the reaction product mixture is treated with a molar deficiency, based on the amount of acid chloride (3), of at least one compound selected from the group consisting of alcohols of the formula (5) and amines of the formula (6).

10. The method according to claim 9, wherein the reaction product mixture is treated with a 0.2 to 0.7-fold molar amount, based on the amount of acid chloride (3), of at least one compound selected from the group consisting of alcohols of the formula (5) and amines of the formula (6).

11. The method according to claim 8, wherein the at least one alcohol of the formula (5) is selected from the group consisting of methanol, ethanol and n-propanol.

12. The method according to claim 8, wherein the reaction mixture treated with at least one compound selected from the group consisting of alcohols of the formula (5) and amines of the formula (6), is treated over a period of 10 min to 3 h.

13. The method according to claim 8, further comprising recrystallizing the astaxanthin diester of formula (1) from another solvent or a mixture of two or more solvents.

14. The method according to claim 8, further comprising adding water to the reaction product mixture following treatment with the at least one compound selected from the group consisting of alcohols of the formula (5) and amines of formula (6).

15. The method according to claim 14, wherein following the addition of the water, the reaction product mixture is subjected to an acidic work-up; and the reaction product of the formula (1) is crystallized from another solvent or a mixture of two or more solvents.

16. (canceled)

17. An astaxanthin diester of formula (1) for therapeutic use as a medicament, or as an ingredient for a medicinal preparation, in which R is a residue selected from the group consisting of C13-C19-alkyl, C13-C19-alkenyl, C13-C19-alkdienyl and C13-C19-alktrienyl.

Description

[0077] Further characteristics, details and advantages of the invention are apparent from the wording of the claims and also from the working examples described below and also comparative examples by reference to the tables and figures. The figures show:

[0078] FIG. 1: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitic acid, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC) and N,N-dimethylaminopyridine (DMAP).

[0079] FIG. 2: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitic acid, N,N-diisopropylcarbodiimide (DIC) and N,N-dimethylaminopyridine (DMAP).

[0080] FIG. 3: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitic acid, propylphosphonic anhydride and N,N-diisopropylethylamine (DIPEA).

[0081] FIG. 4: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitic acid, 1,1-carbonyldiimidazole (CDI) and acetic acid.

[0082] FIG. 5: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, vinyl palmitate, Novozyme 435 and acetonitrile.

[0083] FIG. 6: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitoyl chloride and N-methylimidazole.

[0084] FIG. 7: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitoyl chloride, N,N-dimethylaminopyridine (DMAP) and alkylamine base.

[0085] FIG. 8: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitoyl chloride and 3-methylpyridine (3-picoline).

[0086] FIG. 9: Thin-layer chromatogram (TLC) of the reaction of astaxanthin 2, palmitoyl chloride, pyridine or diisopropylethylamine (DIPEA) or triethylamine (TEA).

[0087] Comparative examples relating to the reaction of astaxanthin 2 with a free carboxylic acid

[0088] A free carboxylic acid is understood to mean a carboxylic acid of the general formula 7

##STR00006##

in which R is a residue selected from the group consisting of C9-C19-alkyl, C9-C19-alkenyl, C9-C19-alkdienyl, C9-C19-alktrienyl, where these terms are as already defined in the text above.

COMPARATIVE EXAMPLE 1: REACTION OF ASTAXANTHIN 2 WITH PALMITIC ACID IN THE PRESENCE OF EDC

[0089] 3 g (11.7 mmol) of palmitic acid were charged in 47.37 ml (53 g, 740 mmol) of dichloromethane and 3.36 g (17.55 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC) was added at room temperature over 5 minutes. After 2 hours, 3.49 g (5.85 mmol) of astaxanthin 2 was added at room temperature and the mixture stirred at room temperature overnight. The mixture was heated to reflux for 3 hours, then 142.93 mg (1.17 mmol) of 4-dimethylaminopyridine DMAP was added, the mixture boiled under reflux a further 4 hours and then stirred overnight. The conversion to astaxanthin dipalmitate was evaluated by thin-layer chromatography (cyclohexane/ethyl acetate=1:2) and by HPLC.

[0090] FIG. 1 shows that no reaction of any sort can be detected after 3 hours and even after 7 hours. Even the formation of astaxanthin monopalmitate, i.e. the corresponding monoester of astaxanthin 2, does not occur.

COMPARATIVE EXAMPLE 2: REACTION OF ASTAXANTHIN 2 WITH PALMITIC ACID IN THE PRESENCE OF DIC

[0091] 3 g (11.7 mmol) of palmitic acid were charged in 47.37 ml (53 g, 740 mmol) of dichloromethane and 2.21 g (17.55 mmol) of N,N-diisopropylcarbodiimide (DIC) was added at room temperature over 5 minutes. After 2 hours, 142.93 mg (1.17 mmol) of 4-dimethylaminopyridine (DMAP) and 2.3 g (3.86 mmol) of astaxanthin 2 were added and the mixture heated to reflux for 20 hours. After cooling, the conversion to astaxanthin dipalmitate was evaluated by thin-layer chromatography (cyclohexane/ethyl acetate=1:2).

[0092] As can be seen in FIG. 2, even after 20 h large proportions of astaxanthin 2 are unreacted, a further large proportion reacted to give astaxanthin monopalmitate and only a fraction of astaxanthin 2 used formed astaxanthin dipalmitate.

[0093] Similar results were obtained when retinoic acid or dihomo-gamma-linolenic acid (DGLA) or gamma-linolenic acid (GLA) were used instead of palmitic acid under otherwise identical conditions.

COMPARATIVE EXAMPLE 3: REACTION OF ASTAXANTHIN 2 WITH PALMITIC ACID IN THE PRESENCE OF PPA

[0094] 1.08 g (4.2 mmol) of palmitic acid and 2.39 g (4.0 mmol) of astaxanthin 2 were charged in 25.56 ml (34 g, 400.32 mmol) of dichloromethane. At 0 to 5° C., 3.18 g (5 mmol) of a 50 percent by weight solution of propylphosphonic anhydride solution (PPA) In DMF and then over 3 minutes 1.81 g (14 mmol) of diisopropylethylamine (DIPEA) were added dropwise. The mixture was then stirred for 35 minutes at 0 to 5° C., brought to room temperature and stirred overnight. After said 35 minutes and after 20 hours, the conversion to astaxanthin dipalmitate was evaluated by thin-layer chromatography (cyclohexane/ethyl acetate=1:2).

[0095] It can be seen from FIG. 3 that no reaction took place either after 35 minutes or after 20 hours. Not even traces of astaxanthin monopalmitate can be detected after 20 hours.

COMPARATIVE EXAMPLE 4: REACTION OF ASTAXANTHIN 2 WITH PALMITIC ACID IN THE PRESENCE OF CDI

[0096] 3 g (11.7 mmol) of palmitic acid were charged in 47.37 ml (53 g, 740 mmol) of dichloromethane. 2.85 g (17.55 mmol) of 1,1′-carbonyldiimidazole (CDI) were added at room temperature in three portions at intervals of 5 minutes each. The mixture was stirred overnight and 3.49 g (5.85 mmol) of astaxanthin 2 were added on the following day. A sample was analyzed by thin-layer chromatography after 6 hours, then 133.8 μl of acetic acid were added and the mixture stirred overnight at room temperature. After 20 hours, a further sample was analyzed by thin-layer chromatography. (Eluent for both chromatograms was cyclohexane/ethyl acetate=1:2.)

[0097] FIG. 4 shows that no astaxanthin dipalmitate forms after 6 hours. At best, traces of astaxanthin monopalmitate are detectable. Even after 20 hours, large amounts of unreacted astaxanthin 2 still remain and a certain fraction of astaxanthin monopalmitate is present. The desired astaxanthin dipalmitate can only be detected in very low amounts.

[0098] Comparative examples relating to the reaction of astaxanthin 2 with a carboxylic ester

COMPARATIVE EXAMPLE 5: REACTION OF ASTAXANTHIN 2 WITH VINYL PALMITATE IN THE PRESENCE OF NOVOZYME 435

[0099] 1.04 g (3.69 mmol) of vinyl palmitate and 1 g (1.68 mmol) of enantiomerically pure 3S,3'S-astaxanthin 2 were charged in 25.45 ml (20 g, 0.49 mmol) of acetonitrile and treated with 1 g of Novozyme 435 (lipase from Candida antarctica Immobilized on acrylic acid resin, CAS Number 9001-62-1, EC Number 232-619-9). This mixture was heated in a water bath to 55° C. (bath temperature 60° C.). A sample was analyzed by thin-layer chromatography after 5 hours at this temperature (eluent: cyclohexane/ethyl acetate=1:2).

[0100] It can be seen from FIG. 5 that no conversion of any sort of the enantiomerically pure astaxanthin 2 to astaxanthin monopalmitate or astaxanthin dipalmitate takes place after 5 hours.

[0101] A similarly poor result was obtained using vinyl acetate instead of vinyl palmitate under otherwise identical conditions.

[0102] Examples relating to the reaction of astaxanthin 2 with an acid chloride

EXAMPLE 1: REACTION OF ASTAXANTHIN 2 WITH PALMITOYL CHLORIDE IN THE PRESENCE OF METHYL IMIDAZOLE

[0103] 2.98 g (5 mmol) of astaxanthin 2 were charged in 25 ml (33.25 g, 391.5 mmol) of dichloromethane and 1.32 ml (1.35 g, 16.5 mmol) of N-methylimidazole was added in one portion at room temperature. 4.12 g (15 mmol) of palmitoyl chloride was added dropwise over 2 minutes at 20-28° C. and the heat liberated by the exothermic reaction was removed via an ice bath. A further 25 ml (33.25 g, 391.5 mmol) of dichloromethane were added to the mixture which was stirred at room temperature for 2.5 hours and then stirred overnight. Samples taken after 2.5 hours and after 20 hours were analyzed by thin-layer chromatography (eluent: cyclohexane/ethyl acetate=1:2).

[0104] It can be seen in FIG. 6 that even after 2.5 hours a large proportion of astaxanthin 2 has been converted to the corresponding astaxanthin dipalmitate and a further proportion to astaxanthin monopalmitate. After 20 hours, only astaxanthin dipalmitate is found.

EXAMPLE 2: REACTION OF ASTAXANTHIN 2 WITH PALMITOYL CHLORIDE IN THE PRESENCE OF N,N-DIMETHYLAMINOPYRIDINE (DMAP) AND AN ALKYLAMINE BASE

[0105] 0.25 g (0.42 mmol) of astaxanthin 2 were charged in 2.09 ml (2.79 g, 30 mmol) of dichloromethane in example 2a and example 2b respectively. In example 2a, 140 mg (192.66 μl, 1.38 mmol) of triethylamine (TEA) and 5.12 mg (0.04 mmol) of N,N-dimethylaminopyridine (DMAP) were added in one portion and likewise in example 2b, 180 mg (240.77 μl, 1.38 mmol) of N,N-diisopropylethylamine (DIPEA) and 5.12 mg (0.04 mmol) of N,N-dimethylaminopyridine (DMAP) were added in one portion. Then, 380 μl (350 mg, 1.26 mmol) of palmitoyl chloride was added in each case in example 2a and example 2b and the mixture was left to stir overnight. The formation of astaxanthin dlpalmitate was investigated by thin-layer chromatography after 5 hours (eluent: cyclohexane/ethyl acetate=1:2).

[0106] It can be seen from FIG. 7 that a large proportion of astaxanthin dipalmitate has already been formed after 5 hours using triethylamine (TEA) with catalytic amounts of N,N-dimethylaminopyridine (DMAP) (example 2a), whereas no notable amounts of astaxanthin dipalmitate can be detected after 5 hours using N,N-diisopropylethylamine (DIPEA) and N,N-dimethylaminopyridine (DMAP).

EXAMPLE 3: REACTION OF ASTAXANTHIN 2 WITH PALMITOYL CHLORIDE IN THE PRESENCE OF 3-METHYLPYRIDINE (3-PICOLINE)

[0107] 0.25 g (0.42 mmol) of astaxanthin 2 were charged in 2.09 ml (2.79 g, 30 mmol) of dichloromethane. 130 mg (134.51 μl, 1.38 mmol) of 3-methylpyridine were added in one portion. Then, 380 μl (350 mg, 1.26 mmol) of palmitoyl chloride was added and the mixture was left to stir overnight. The formation of astaxanthin dipalmitate was investigated by thin-layer chromatography after 4 hours and 20 hours (eluent: cyclohexane/ethyl acetate=1:2).

[0108] FIG. 8 distinctly shows that astaxanthin 2 is already completely converted to astaxanthin dipalmitate after 4 hours and that nothing changes also after 20 hours.

EXAMPLE 4: REACTION OF ASTAXANTHIN 2 WITH PALMITOYL CHLORIDE IN THE PRESENCE OF PYRIDINE OR DIISOPROPYLETHYLAMINE (DIPEA) OR TRIETHYLAMINE (TEA)

[0109] 0.25 g (0.42 mmol) of astaxanthin 2 was charged in 2.09 ml (2.79 g, 30 mmol) of dichloromethane for examples 4A, 4B and 4D in each case and in 4.19 ml (5.57 g, 70 mmol) of dichloromethane for example 4E. In example 4A 110 mg (111.34 μl, 1.38 mmol) of pyridine, in example 4B 180 mg (240.77 μl, 1.38 mmol) of N,N-diisopropylamine (DIPEA) and in examples 4D and 4E respectively 140 mg (192.66 μl, 1.38 mmol) of triethylamine (TEA) were added in one portion in each case. Then, 380 μl (350 mg, 1.26 mmol) of palmitoyl chloride was added in each case in all examples and the mixture was left to stir at room temperature. The formation of astaxanthin dipalmitate was investigated by thin-layer chromatography after 4 hours (eluent: cyclohexane/ethyl acetate=1:2).

[0110] The second application in FIG. 9 shows a sample from example 4A taken after 4 hours where it can be seen that, after this time, astaxanthin 2 has already completely converted to the corresponding astaxanthin dipalmitate. In example 4B, using diisopropylethylamine (DIPEA) as base, only a low conversion has taken place at this time point. Examples 4D and 4E, using triethylamine (TEA) as base, which differ only in the amount of dichloromethane used as organic solvent, show that astaxanthin dipalmitate has already formed after 4 hours but that the reaction has not yet gone to completion.

EXAMPLE 5: DETERMINATION OF THE OPTIMAL MOLAR RATIO OF ASTAXANTHIN 2 TO ACID CHLORIDE 3

[0111] In examples 5a, 5b, 5c and 5d, 0.4 g (0.67 mmol) of astaxanthin 2 was in each case charged in 3.35 ml (4.46 g, 52.48 mmol) of dichloromethane and 0.17 g (178.51 μl, 2.21 mmol) of pyridine was added in each case. Then, 550 mg (609.99 μl, 2.01 mmol) of palmitoyl chloride was added in example 5a, 520 mg (569.32 μl, 1.89 mmol) of palmitoyl chloride in example 5b, 480 mg (528.66 μl, 1.75 mmol) of palmitoyl chloride in example 5c and 440 mg (487.99 μl, 1.60 mmol) of palmitoyl chloride in example 5d. The mixtures were allowed to react for 5 hours and a sample from each example was analyzed by HPLC under the following conditions

[0112] Column: Zorbax Eclipse XDB-C18 1.8 μm 50*4.6 mm from Agilent®

[0113] Eluent: -A: 0.05% by volume triethylamine in water [0114] B: tetrahydrofuran

TABLE-US-00001 Time Flow rate [min] % B [ml/min] 0.0 40 1.2 8.0 100 1.2 10.0 100 1.2 10.1 40 1.2
Detector: UV detector λ=470 nm, BW=50 nm
Flow rate: 1.2 ml/min

Injection: 5 μl

Temperature: 50° C.

[0115] Run time: 12 min

Pressure: ca. 260 bar

[0116] The results are presented in Table 1 below.

TABLE-US-00002 TABLE 1 Astaxanthin Astaxanthin Astaxanthin monopalmitate dipalmitate RT 3.2 RT 5.3 RT 6.5 Example [area %] [area %] [area %] 5A 0 0.63 92.48 5B 0.09 2.50 90.54 5C 0.12 2.82 89.22 5D 1.51 9.12 81.79

[0117] It can be seen that astaxanthin 2 elutes at a retention time of 3.2 minutes, astaxanthin monopalmitate at a retention time of 5.3 minutes and astaxanthin dipalmitate at a retention time of 6.5 minutes. Example 5a affords the best result. According to the integrated peaks, 92.48% of astaxanthin dipalmitate and 0.63% of astaxanthin monopalmitate are obtained. The astaxanthin 2 starting material is no longer present. Therefore, a particularly good yield of astaxanthin dipalmitate is obtained when the molar ratio of palmitoyl chloride to astaxanthin 2 is 3.

EXAMPLE 6: SYNTHESIS OF ASTAXANTHIN DIDECANOATE

[0118] 10 g (16.75 mmol) of astaxanthin 2 and 4.37 g (55.29 mmol) of pyridine are charged in 111.4 g of dichloromethane and 10.65 g (50.26 mmol) of decanoyl chloride are added dropwise at 20° C. over 5 minutes. The reaction mixture is allowed to react overnight, the mixture diluted with 111.4 g of dichloromethane, 0.54 g of methanol and, 30 min later, 16.8 g of water are added and the phases separated. The lower phase is washed with 17.59 g of 10% hydrochloric acid and then twice with 16.75 g of water. The organic phase is rotary evaporated at 50° C., the residue is taken up in ca. 250 ml of t-butyl methyl ether and again fully concentrated. The residue is dissolved in 67 ml of t-butyl methyl ether and 201 ml of ethanol is added dropwise. The mixture is heated to 45° C. and then cooled to 0° C. over 17 h. The precipitated crystalline solid is filtered off under suction, washed twice with 150 ml of ethanol each time and dried at 40° C. in a vacuum drying cabinet. 10.4 g (69% yield) of astaxanthin didecanoate (m.p. 104.8° C.) are obtained.

EXAMPLE 7: SYNTHESIS OF ASTAXANTHIN DIDODECANOATE

[0119] 10 g (16.75 mmol) of astaxanthin 2 and 4.37 g (55.29 mmol) of pyridine are charged in 111.4 g of dichloromethane and 12.2 g (50.26 mmol) of dodecanoyl chloride are added dropwise at 20° C. over 5 minutes. The reaction mixture is allowed to react overnight, the mixture diluted with 111.4 g of dichloromethane, 0.54 g of methanol and, 30 min later, 16.8 g of water are added and the phases separated. The lower phase is washed with 17.59 g of 10% hydrochloric acid and then twice with 16.75 g of water. The organic phase is rotary evaporated at 50° C., the residue is taken up in ca. 250 ml of t-butyl methyl ether and again fully concentrated. The residue is virtually dissolved in 117 ml of t-butyl methyl ether at 67° C. and 201 ml of ethanol is added dropwise. The mixture is initially cooled to 45° C. and then to 0° C. over 17 h. The precipitated crystalline solid is filtered off under suction, washed twice with 200 ml of ethanol each time and dried at 40° C. in a vacuum drying cabinet. 11.7 g (73% yield) of astaxanthin didodecanoate (m.p. 130.0° C.) are obtained.

EXAMPLE 8: SYNTHESIS OF ASTAXANTHIN DIHEXADECANOATE

[0120] 7.6 g (12.7 mmol) of astaxanthin and 2.98 g (37.7 mmol) of pyridine are charged in 75.9 g of dichloromethane and 9.42 g (34.3 mmol) of hexadecanoyl chloride are added dropwise at 20° C. over 5 minutes. The reaction mixture is allowed to react overnight, the mixture diluted with 75.9 g of dichloromethane, 0.37 g of methanol and, 30 min later, 11.4 g of water are added and the phases separated. The lower phase is washed with 11.4 g of 10% hydrochloric acid and then twice with 11.4 g of water. The organic phase is rotary evaporated at 50° C., the residue is taken up in ca. 217 ml of t-butyl methyl ether and again fully concentrated. The residue is virtually dissolved in 217 ml of ethyl acetate at 50° C. and 108 ml of ethanol is added dropwise. The mixture is initially cooled to 45° C. and then to 0° C. over 17 h. The precipitated crystalline solid is filtered off under suction, washed twice with 72 ml of ethanol each time and dried at 40° C. in a vacuum drying cabinet. 10 g (73% yield) of astaxanthin dihexadecanoate (m.p. 79.7° C.) are obtained.

EXAMPLE 9: SYNTHESIS OF ASTAXANTHIN DIOCTADECANOATE

[0121] 10 g (16.75 mmol) of astaxanthin and 4.37 g (55.29 mmol) of pyridine are charged in 111.4 g of dichloromethane and 16.9 g (50.26 mmol) of octadecanoyl chloride are added dropwise at 20° C. over 5 minutes. The reaction mixture is allowed to react overnight, the mixture diluted with 111.4 g of dichloromethane, 0.54 g of methanol and, 30 min later, 16.8 g of water are added and the phases separated. The lower phase is washed with 17.59 g of 10% hydrochloric acid and then twice with 16.75 g of water. The organic phase is rotary evaporated at 50° C., the residue is taken up in ca. 250 ml of t-butyl methyl ether and again fully concentrated. The residue is dissolved in 67 ml of t-butyl methyl ether and 201 ml of ethanol at 53° C. The mixture is cooled to 45° C., seeded and then cooled to 0° C. over 17 h. The precipitated crystalline solid is filtered off under suction, washed twice with 200 ml of ethanol each time and dried at 40° C. in a vacuum drying cabinet. 15.1 g (80% yield) of astaxanthin dioctadecanoate (m.p. 70.5° C.) are obtained.

[0122] The method according to the invention is not however, limited to any of the embodiments described above, but is applicable in a variety of ways.

[0123] This disclosure presents an environmentally friendly, sustainable and cost-effective method for preparing astaxanthin diesters of the formula 1, in which astaxanthin of the formula 2 is doubly esterified with fatty acid chlorides of the general formula 3. For this purpose, compound 2 and 3 are reacted in an organic solvent in the presence of a nitrogen-containing base of the general formula 4. The invention further relates to the non-therapeutic use of the diester 1, in which R is a residue selected from the group consisting of C13-C19-alkyl, C13-C19-alkenyl, C13-C19-alkdienyl and C13-C19-alktrienyl, in human or animal nutrition and also the therapeutic use of the diester 1 prepared according to the method as a medicament and also as an ingredient in a medicinal preparation.