METHOD FOR PRODUCING ASTAXANTHIN FROM ASTACIN

Abstract

The invention relates to a method for the non-stereoselective and also for the stereoselective synthesis of astaxanthin from astacin. For this purpose, a reducing agent is used selected from the group of hydrogen, a secondary alcohol, formic acid and also the salts of formic acid or from a mixture of at least two representatives of the compound classes stated above. The invention further relates to the use of astacin as starting compound for the synthesis of astaxanthin.

Claims

1-15. (canceled)

16. A method for preparing astaxanthin of the formula (1) ##STR00024## in which the asymmetric center in position 3 and 3′ is racemic or each has (S) or (R) configuration and the exocyclic double bonds have either E or E and/or Z configuration, wherein astacin of the formula (2), ##STR00025## in which the exocyclic double bonds have either E or E and/or Z configuration, is reacted non-stereoselectively or stereoselectively with a reducing agent.

17. The method according to claim 16, wherein the reducing agent is at least one compound selected from the group consisting of hydrogen gas; a secondary alcohol, formic acid or the salts of formic acid.

18. The method according to claim 16, wherein the reducing agent is at least one compound selected from the group consisting of hydrogen gas; isopropanol; butan-2-ol; formic acid, an alkali metal, alkaline earth metal or ammonium formate or a mono-, di-, tri- or tetra(C1-C4)-alkylammonium formate.

19. The method according to claim 16, where in the astacin (2) is reacted non-stereoselectively or stereoselectively with the reducing agent in the presence of a transition metal catalyst.

20. The method according to claim 16, wherein the astacin (2) is reacted non-stereoselectively or stereoselectively with the reducing agent in the presence of an achiral or optically active transition metal catalyst.

21. The method according to claim 18, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag and Au.

22. The method according to claim 18, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Ru, Ir, Ni and Pd.

23. The method according to claim 18, wherein the transition metal catalyst comprises at least one ligand selected from amines and/or phosphanes.

24. The method according to claim 23, wherein the ligand is a phosphane of the general formula (3), ##STR00026## where R, R′ and R″ are each independently selected from the group consisting of at least one of the residues C1-C4-alkyl, phenyl, mono- up to tri-C1-C4-alkyl-substituted aryl; and a triarylphosphane.

25. The method according to claim 23, wherein the ligand is a phosphane of the general formula (3), ##STR00027## where R, R′ and R″ are each independently selected from the group consisting of a triphenylphosphane.

26. The method according to claim 18, where in the transition metal catalyst comprises at least one ligand selected from the group consisting of H.sub.2N—CH.sub.2—CH.sub.2—OH, MeHN—CH.sub.2—CH.sub.2—OH, H.sub.2N—CH.sub.2—CH.sub.2—NH.sub.2, TsNH—CH.sub.2—CH.sub.2—NH.sub.2, TsNH—CH.sub.2—CH.sub.2—NH—(CH.sub.2).sub.n—O.sub.m—(CH.sub.2).sub.o-aryl where n=1-4, m=0 or 1 and o=1-4 and aryl=phenyl or mono-, di-, tri-C1-C4-alkylphenyl, optically active compound.

27. The method according to claim 18, wherein the transition metal catalyst comprises at least one ligand selected from the group consisting of an optically active amine.

28. The method according to claim 18, wherein the transition metal catalyst comprises at least one ligand selected from the group consisting of H.sub.2N—CHPh-CHPh-OH, H.sub.2N—CHMe-CHPh-OH, MeHN—CHMe-CHPh-OH, TsNH—CHPh-CHPh-NH.sub.2, (1S,2S)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine, (1R,2R)—N-p-toluenesulfonyl-1,2- diphenylethylenediamine, N-[(1S,2S)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzene sulfonamide and N-[(1R,2R)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzene sulfonamide.

29. The method according to claim 20, wherein the ligand is deprotonated.

30. The method according to claim 19, wherein the transition metal is applied to a solid support comprising at least one substance selected from the group consisting of carbon, aluminum oxide and silicon dioxide.

31. The method according to claim 16, wherein the astacin (2) is reacted non-stereoselectively or stereoselectively with a reducing agent under basic conditions.

32. The method according to claim 16, wherein the astacin (2) is reacted non-stereoselectively or stereoselectively with a reducing agent in a liquid medium.

33. The method according to claim 32, wherein said liquid medium comprising more than 50% by volume of at least one organic solvent and said organic solvent comprises at least one compound selected from the group consisting of dichloromethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, acetonitrile, ethylene carbonate and propylene carbonate.

34. The method according to claim 16, wherein the astacin (2) is reacted non-stereoselectively or stereoselectively with a reducing agent at a temperature of 10° C. to 85° C.

35. An intermediate for preparing (3R/S, 3′R/S)-astaxanthin (1a) ##STR00028## which comprises utilizing the astacin (2) ##STR00029## wherein the exocyclic double bonds in (1a) have either E or E and/or Z configuration and/or (3S, 3′S)-astaxanthin (1b), wherein the exocyclic double bonds in (1b) have either E or E and/or Z configuration ##STR00030## and/or (3R, 3′R)-astaxanthin (1c), wherein the exocyclic double bonds in (1c) have either E or E and/or Z configuration ##STR00031##

Description

EXAMPLES

Example 1

Synthesis of (3S,3′S)-astaxanthin (3S,3′S)-1 from astacin 2

[0100] 0.5 g (0.8 mmol) of astacin 2 are charged in 20 ml of dichloromethane at 22° C., 1.01 g (10.02 mmol) of triethylamine and 5.1 mg (0.01 mmol) of chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) are added, 0.37 g (8.01 mmol) of formic acid are added dropwise and the mixture is heated to 40° C. for 7.5 h. After cooling to 20° C., 10 ml of water are added, the phases separated and the organic phase washed with 10 ml of water. The organic phase is then concentrated on a rotary evaporator. The residue is suspended in 2.7 ml of methanol and heated to 106° C. for 4 h and then concentrated again. 0.523 g (71.38% strength, yield: 78%) of (3S,3′S)-astaxanthin 1b are obtained with a diastereomeric excess of 98% and an enantiomeric excess of >99%.

Example 2

Synthesis of (3R/S,3′R/S)-astaxanthin (3R/S,3′R/S)-1 from astacin 2

[0101] 1.0 g (1.67 mmol) of astacin 2 are charged in 20 ml of dichloromethane at 22° C., 2.11 g (20.85 mmol) of triethylamine and 8.09 mg (0.02 mmol) of chloro{[2-aminoethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) are added, 0.77 g (16.68 mmol) of formic acid are added dropwise and the mixture is heated to 40° C. for 4.5 h. After cooling to 20° C., 15 ml of water are added, the phases separated and the organic phase washed with 15 ml of water. The organic phase is then concentrated on a rotary evaporator. The residue is suspended in 6 ml of methanol heated to 106° C. for 4 h and then concentrated again. 0.72 g (88.1% strength, yield: 63.7%) of (3R/S,3′R/S)-astaxanthin 1a are obtained.

Example 3

[0102] 2.0 g (3.31 mmol) of astacin 2 are charged in 40 ml of dichloromethane at 22° C., 4.19 g (41.4 mmol) of triethylamine and 21.1 mg (0.03 mmol) of chloro{[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) are added and 1.51 g (33.1 mmol) of formic acid are added dropwise at 22-35° C. The reaction mixture is heated to 40° C. for 7 h. 15 ml of water is added to the mixture and the phases are separated. The organic phase is washed with 40 ml of 10% strength acetic acid and 40 ml of saturated sodium hydrogen carbonate solution and then concentrated on a rotary evaporator. The residue is suspended in 12 ml of methanol heated to 106° C. for 4 h and, after cooling to 0° C., filtered off, washed with 3 ml of methanol and dried in a vacuum drying cabinet at 20° C. 1.21 g (93.3% strength, yield: 57%) of (3R,3R)-astaxanthin 1c are obtained with a diastereomeric excess of 97% and an enantiomeric excess of >99%.

[0103] It is evident that the invention relates to a method for the non-stereoselective and also for the stereoselective synthesis of astaxanthin from astacin. For this purpose, a reducing agent is used selected from the group of hydrogen, a secondary alcohol, formic acid and also the salts of formic acid or from a mixture of at least two representatives of the compound classes stated above. The invention further relates to the use of astacin as starting compound for the synthesis of astaxanthin.