Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
  • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/09—Geometrical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the present invention relates to a process for preparing 6-hydroxy-3-[3-hydroxy-3- methyl-penta-1 ,4-dienyl]-2,4,4-trimethyl-cyclohexa-2,5-dien-1 -one of the formula (I).
• the invention also relates to 6-hydroxy-3-[3-hydroxy-3-methyl-penta-1 ,4-dienyl]-2,4,4- trimethyl-cyclohexa-2,5-dien-1 -one having a high E/Z-ratio of at least 80:20 and to the use thereof as a starting material for the preparation of astaxanthin or astacene.
• Astaxanthin (3,3'-dihydroxy-p,p-carotene-4,4'-dione) and its dehydroanalogue astacene are naturally occurring red carotenoid pigments which are described by the formulae below (only the all-trans isomer are shown).
• Astaxanthine hereinafter AXT
• AXT is used as feed component for various animals, in particular for lobster, salmon and trout.
• AXT has a vitamin-like activity acting as a result beneficially on the fertility and immune defense of the fish in breeding farms.
• AXT is permitted as feed additives to the fish food during the production of edible fish.
• AXT is also used as food dye, as nutriceutical or cosmetics additive having antioxidant properties.
• AXT can protect the skin against the stress caused by UV radiation and acts in this function considerably more strongly than vitamin E.
• AXT supplements the protective action of sunscreen agents and cannot be washed off. Studies on animals permit the hypothesis that AXT lowers the blood sugar level and improves various parameters of the metabolic syndrome.
• Astaxanthin can also be obtained on an industrial scale from blood-rain alga
• Astaxanthin is generally obtained by extraction by means of dichloromethane (see, e.g.
• Astacene was found in the 1930's when isolating carotenoids from biologic materials. Its constitution was described by P. Karrer et al., Helv. Chim. Acta 17, 745 (1934) and Helv. Chim. Acta 18, 96 (1935). An efficient synthesis of astacene starting from
• 6-oxoisophoron was described by Widmer et al., Helv. Chim. Acta 65, 671 (1982). Its occurrence in biological material was confirmed in 2003 (J, Phycol. Suppl. 1 , 39, 36 (2003), isolation from green algae Paimeiiococcus miniatus). There is a certain interest in astacene as a starting material for astaxanthin, from which the latter should be obtainable by hydrogenation.
• the central key-step in the syntheses of both astaxanthin and astacene is the coupling of the compound of the formula (III) in the form of its C15-phosphonium salt (Ilia) or its phenylsulfonyl analogue (1Mb), with a C10-dialdehyde (IV) 2,7-dimethyloctatrienedial of the formula (IV) as depicted in the scheme 1 below.
• the compounds (Ilia) and (1Mb) can be obtained from suitable precursors, where X is OH (compound (III c)) or halogen, such as Br (compound (llld)).
• X is P(Phenyl) 3 Br (Ilia) or Phenyl-S0 2 (1Mb)
• the key step is the base induced isomerization of an acetylenic C15 precursor compound of the formula (V) in methanolic potassium hydroxide as depicted in scheme 2.
• methanolic potassium hydroxide methanolic potassium hydroxide
• WO 2016/023772 describes a process for the selective hydrogenation of the compound of the formula (I) resulting in high yields of 6-hydroxy-3-[(1 E/Z)-3-hydroxy-3-methyl- penta-1 ,4-dienyl]-2,4,4-trimethyl-cyclohex-2-en-1 -one, hereinafter compound (VII).
• the compound of the formula (VII) is suggested as a suitable C15-precursor for the preparation of astaxanthin.
• WO 2016/023772 does not describe how to prepare the compound of formula (I), let alone how to prepare the compound of formula (I) having a high E/Z- ratio with regard to the exocyclic double bond in the 1 -position of the 3-hydroxy-3- methylpenta-1 ,3-dienyl side chain.
• the process should also provide the desired compound of the formula (I), in particular the compound of the formula (l-E) in at least acceptable yields. It was surprisingly found that the acetylenic C15-compound 6-hydroxy-3-(3-hydroxy-3- methyl-pent-4-en-1 -ynyl)-2,4,4-trimethyl-cyclohex-2-en-1 -one of the formula (II) can be isomerized to the compound of the formula (I) with acceptable to good yields by action of a base. Moreover, it was found that the E-isomer of the formula (l-E) is formed with high selectivity, resulting in the compound of formula (I) with a E/Z-ratio of at least 80:20, in particular at least 90:10. In fact, in most cases the Z-isomer (l-Z) is not observed at all.
• the present invention relates to a process for preparing a compound of the formula (I), in particular a compound of the formula (l-E) which comprises the reaction of a compound of the formula (II) with a base.
• the present invention also relates to the E-isomer of (I), i.e. to the compound of the formula (l-E), and to mixtures of its E-isomer and its Z-isomer, i.e. mixtures of the compound the formula (l-E) and the compound of the formula (l-Z), where the E/Z-ratio is at least 80:20, in particular at least 90:10.
• the compound of the formula (I), in particular in the form of the compound of the formula (l-E), and also in the form of mixtures of the compound of the formula (l-E) and the compound of the formula (l-Z), where the E/Z-ratio is at least 80:20, in particular at least 90:10, are particularly useful as C15 precursors in the synthesis of astacene and also in the synthesis of astaxanthin. Therefore, the present invention also relates to the use of the compound of formula (I), which has a E/Z-ratio with regard to its 1 E-isomer l-E and its 1 Z-isomer l-Z of at least 80:20, in particular at least 90:10, as an
• the compound of formula (I), in particular the compound of the formula (l-E), as well as mixtures of the compound of the formula (l-E) and the compound of the formula (l-Z), where the E/Z-ratio is at least 80:20, in particular at least 90:10, can be selectively reduced to the compound of the formula (VII) by the method described in WO 2016/023772 with selectivity regarding the endocyclic double bond and without noticeable occurrence of E/Z-isomerization.
• the present invention also relates to a method for preparing a compound of the formula (VII), in particular a compound of the formula (VII) having a E/Z-ratio with regard to its 1 E-isomer VI l-E and its 1 Z-isomer VI l-Z of at least 80:20, in particular at least 90:10, which comprises
• alkyl and cycloalkyl are understood as collective terms for individual listings of the individual group members.
• the prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
• alkyl denotes in each case a straight-chain or branched saturated aliphatic group having usually from 1 to 6 carbon atoms, and in particular from 1 to 4 carbon atoms.
• Examples of Ci-C4-alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl (sec-butyl), isobutyl and tert-butyl.
• Ci-C6-alkyl examples are, apart from those mentioned for Ci-C4-alkyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethyl propyl, n-hexyl, 1 ,1 -dimethylpropyl,
• cycloalkyl relates to a monocyclic or bicyclic cycloaliphatic group having usually from 3 to 8 carbon atoms, in particular 5 or 6 carbon atoms, examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1 ]hexyl, bicyclo[2.2.1 ]heptyl, bicyclo[3.1 .1 ]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl.
• alkanolate is understood as the salts of alkanols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, tert.-butanol, n-pentanol, 2-pentanol, 2-methyl-1 -butanol, 2,2-dimethylpropan-1 -yl and n-hexanol.
• aryl is understood as an unsaturated mono- or polycyclic hydrocarbon group having at least one benzene ring, examples including phenyl, indanyl and naphthyl.
• the compound of the formula (I) is prepared by reaction of a compound of the formula (II) with a base.
• Suitable bases include, for example, oxo bases of alkali metals, oxo bases of alkaline earth metals, amide bases of alkali metals, amide bases of alkaline earth metals and tertiary amines.
• Suitable oxo bases of alkalimetals and of alkaline earth metals are e.g. alkoholates, in particular C1-C6 alkanolates of alkalimetals and C1-C6 alkanolates of alkaline earth metals, the hydroxides of alkalimetals, the hydroxides of alkaline earth metals and the oxides of alkaline earth metals.
• Suitable oxo bases of alkalimetals and alkaline earth metals include, but are not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium oxide, lithium C1-C6 alkanolates, such as lithium methanolate (lithium methoxide), lithium ethanolate, lithium propanolate, lithium isopropanolate, lithium n-butanolate and lithium tert.-butanolate, sodium C1-C6 alkanolates, such as sodium methanolate
• potassium methoxide sodium methoxide
• sodium ethanolate sodium propanolate
• sodium isopropanolate sodium n-butanolate and sodium tert.-butanolate
• potassium C1-C6 alkanolates such as potassium methanolate (potassium methoxide), potassium ethanolate, potassium propanolate, potassium isopropanolate, potassium n-butanolate and potassium tert.-butanolate and magnesium C1-C6 alkanolates, such as magnesium methanolate and magnesium ethanolate.
• Suitable amides of alkalimetals and alkaline earth metals are e.g. the amides themselves, i.e. the compounds bearing the NH2 anion, and dialkylamides, in particular the di-Ci-C6-alkylamides of alkalimetals and of alkaline earth metals, especially the di-Ci-C6-alkylamides of lithium, sodium or potassium.
• suitable amides of alkalimetals and alkaline earth metals include, but are not limited to sodium amide, potassium amide, lithium diethylamide, sodium diethylamide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, etc.
• Suitable tertiary amines are in particular amines of the formula (A)
• R a , R b and R c each independently are selected from the group consisting of Ci-C6-alkyl, Cs-Cs-cycloalkyl, phenyl and phenyl, which is substituted by 1 , 2, or 3
• Ci-C4-alkyl radicals, or R a and R b form a saturated N-heterocycle, which in addition to the tertiary nitrogen atom may have a further heteroatom or heteroatom group selected from O, S and N-R x , where R x is d-Ce-alkyl, as a ring member, or R a , R b and R c together with the nitrogen atom form a 8 to 12 membered N-heterobicycle, in particular a 8 to 12 membered N-heterobicycle, where the tertiary heteroatom is part of an endocyclic amidine group.
• tertiary amines include, but are not limited to tri-Ci-C6-alkyl amines, such as trimethylamine, methdiethylamine,
• oxo bases of alkalimetals in particular to oxo bases of alkalimetals, which are selected from alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal alkoholates, in particular lithium C1-C4-alkanolat.es, sodium C1-C4-alkanolat.es and potassium C1-C4- alkanolates, alkaline earth metal hydroxides, such as calcium hydroxide and magnesium hydroxide and to mixtures thereof.
• alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
• alkali metal alkoholates in particular lithium C1-C4-alkanolat.es, sodium C1-C4-alkanolat.es and potassium C1-C4- alkanolates
• alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide and to mixtures thereof.
• oxo bases include alkaline earth metal oxides and alkaline earth metal alkoholates, in particular alkaline earth metal C1-C4-alkanolat.es.
• alkali metal amides alkali metal di-Ci-C4-alkylamides, such as sodium amide, potassium amide, lithium diethylamide, sodium diethylamide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide and mixtures thereof.
• the base is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.
• the base is selected from alkali metal C1-C4-alkanolat.es, in particular from the group consisting of sodium methanolate, potassium methanolate, potassium n-butanolate and potassium tert.-butanolate.
• the base in catalytic amounts, e.g. in an amount of 0.1 mol, 0.2 mol or 0.5 mol per mol of the compound of the formula (II)
• the base is employed in an amount of at least 0.8 mol, in particular at least 0.9 mol, especially at least 1 mol per mol of the compound of the formula (II).
• the base will be employed in an amount of 0.8 to 6 mol per mol of the compound of the formula (II), in particular in an amount of 0.9 to 5 mol per mol of the compound of the formula (II), especially in an amount from 1 to 3 mol per mol of the compound of formula (II).
• the reaction of the compound of formula (II) with the base is preferably carried out in an organic solvent or in a mixture of an organic solvent and water.
• Suitable organic solvents for carrying out the process of the invention include, but are not limited to following solvents and mixtures thereof:
• C5-C8 aliphatic and cycloaliphatic hydrocarbons such as pentanes, hexanes, cyclohexane, and heptanes,
• aromatic hydrocarbons such as benzene, toluene, xylenes and cymene
• halogenated aliphatic hydrocarbons having 1 to 4 carbon atoms such as dichloromethane, trichloromethane and dichloroethane
• aliphatic and alicyclic ketones having 3 to 8 carbon atoms such as acetone, methylethyl ketone, diethylketone and cyclohexanone,
• aliphatic and alicyclic ethers having 4 to 6 carbon atoms such as diethyl ether, methyl tert. -butyl ether, ethyl tert. -butyl ether, diisopropyl ether, tetrahydrofurane and methyl tetrahydrofurane,
• alkanols having 1 to 6 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, tert.-butanol, n-pentanol, and cyclohexanol.
• the reaction of the compound of the formula (II) with the base is performed in a solvent or solvent mixture, which contains at least one solvent selected from the group consisting of water and d-Cs-alkanols.
• the solvent or solvent mixture contains at least 50% by weight, based on the total weight of the solvent or solvent mixture of at least one solvent selected from the group consisting of water and Ci-C5-alkanols.
• the amount of water in the solvent or solvent mixture if any, does not exceed 50% by weight, especially 20% by weight, based on the total weight of the solvent mixture.
• the reaction of the compound of the formula (II) with the base is performed in a solvent or solvent mixture which is selected from the group consisting of at least one Ci-C5-alkanol and mixtures of at least one d-Cs-alkanol with water, where the amount of water does not exceed 20 vol.-%, based on the total volume of solvent or solvent mixture.
• the reaction of the compound of the formula (II) with the base is frequently performed at a temperature of at least 20°C, in particular at least 40°C and especially at least 60°C.
• the reaction temperature will generally not exceed 180°C.
• the reaction of the compound of the formula (II) with the base is performed at a
• the reaction pressure has no, or only a minor effect on the reaction and is therefore typically in the range of from 700 to 1500 mbar, with lower or higher pressures also being possible.
• the reaction may be carried out in an inert atmosphere, for example on the inert gas, such as nitrogen or argon.
• the reaction times required for reacting the compound of the formula (II) with the base can be determined by a person skilled in the art using routine measures; they are typically in the range of from 30 min to 12 h, in particular in the range of from 60 min to 4 h.
• the compound of the formula (II) will typically be brought into contact with the base in a suitable reaction vessel.
• the reaction may be carried out batch-wise, semi-continuously or continuously.
• the base optionally together with at least a portion of the solvent or solvent mixture as described above, is introduced into a suitable reaction vessel and the compound of formula (II), optionally dissolved in the remainder of the organic solvent, or solvent mixture is added thereto under reaction conditions.
• Suitable reaction vessels will depend in a manner known per se from the way how the reaction is conducted.
• Suitable reaction vessels include, e.g. batch-wise operated stirred tank reactors, continuously operated stirred tank reactors, continuously operated stirred tank reactors in series, and reaction tubes.
• the reaction vessels may be equipped with means for controlling pressure and temperature and also with means for metering the reactants and solvents into the reactor and means for discharging the product from the reaction vessel.
• the product of the reaction is usually subjected to a conventional work-up in order to separate the compound of the formula (I) from the reactants or to isolate the compound of the formula (I).
• Suitable methods for work-up include extraction and crystallization and combinations thereof.
• the reaction mixture is neutralized with an acid, in particular with a carboxylic acid, to a pH of ⁇ pH 7.5, in particular to a pH in the range from pH 5 to pH 7 prior to work-up.
• the thus obtained compound of the formula (I) has a high E/Z-ratio of at least 80:20, in particular at least 90:10. In particular, no noticeable amounts of the E-isomer are obtained, i.e. the E/Z-ratio is > 98:1 or > 99:1 .
• the molar ratio of the compound (I) to the compound (VII) formed in the process of the invention is at least 60:40, frequently at least 70:30, in particular at least 80:20 and especially at least 85:15.
• the compound (VIII) can be easily removed prior to the use of (I) in the preparation of astacene or astaxanthin, respectively. Removal of the compound (VIII) can be achieved by chromatography or by any other conventional techniques. However, in most cases it is not necessary to remove the compound of the formula (VIII). Rather, it is possible to use the mixture of the compound (I) and the compound (VII) in the production of the phosphonium compound of the formula (Ilia), as described below and can be separated from the phosphonium compound (Ilia) at that stage.
• the compound of the formula (I) which has been isolated from the reaction mixture may be further purified, e.g. by crystallization or by chromatography or combinations of both, or it may be used as such in the production of astaxanthin or astacene.
• a further aspect of the invention relates to the use of the compound of formula (I), which has a E/Z-ratio with regard to its 1 E-isomer l-E and its 1 Z-isomer l-Z of at least 80:20, in particular at least 90:10, as an intermediate in the production of astacene or astaxanthin.
• a further aspect of the present invention relates to a method for preparing the compound of the formula (VII) having a E/Z-ratio with regard to its 1 E-isomer VI l-E and its 1 Z-isomer Vll-Z of at least 80:20, in particular at least 90:10, which comprises as a step i) the preparation of the compound of the formula (I) by the process as described above and as a step ii) the reaction of the thus obtained compound of the formula (I) with a reducing agent, which provides hydrogen by the method described in WO 2016/023772, the disclosure of which is included by reference.
• the reducing agent of step ii) is selected from hydrogen, secondary C1-C6- alkanols, formic acid and salts of formic acid, with particular preference given to the latter, which may be used as such or prepared in situ by reacting formic acid with a suitable amine, e.g. a tertiary amine of the formula (I) as described above.
• a suitable amine e.g. a tertiary amine of the formula (I) as described above.
• step i) is preferably performed in the presence of a transition metal catalyst, in particular in the presence of an optically active transition metal catalyst, if it is intended to perform the reduction in a stereoselective manner.
• a transition metal catalyst in particular in the presence of an optically active transition metal catalyst, if it is intended to perform the reduction in a stereoselective manner.
• Suitable transition metal catalysts are described on pages 8 to 10 and in the examples of
• Preferred transition metal catalysts for performing step ii) include at least one transition metal of groups 3 to 12 of the periodic table (lUPAC), in particular at least one transition metal selected from Ru, Ir, Ni and Pd, especially Ru.
• Preferred transition metal catalysts for performing step ii) have at least one amine and/or phosphine ligand. If the ligand is chiral, the reduction of step ii) can be performed in a stereoselective manner.
• Suitable phosphine ligands are those of the formula (P)
• R 1 , R 2 and R 3 each independently are selected from the group consisting of Ci-C6-alkyl, Cs-Ce-cycloalkyl, phenyl and phenyl, which is substituted by 1 , 2, or 3 Ci-C4-alkyl radicals, with preference given to triphenylphosphine.
• Suitable amine ligands are in particular those of the formulae H2N-CH2-CH2-OH, CH3HN-CH2-CH2-OH, H2N-CH2-CH2-NH2, TSNH-CH2-CH2-NH2, TsNH-CH2-CH2-NH-(CH2)n-Om-(CH 2 )o-Aryl, H 2 NCHPh-CHPh-OH, H 2 N-CH(CH 3 )-CHPh-OH, CH 3 HN-CH(CH 3 )-CHPh-OH,
• n is an integer from 1 to 4
• m is 0 or 1
• o is an integer from 1 to 4
• Ph indicates a phenyl group
• Ts is a toluenesulfonyl group
• aryl indicates phenyl, which is unsubstituted or carries 1 , 2, or 3 Ci-C4-alkyl radicals.
• the catalyst can be prepared in situ from a suitable precursor, by reacting the precursor with the ligand.
• suitable precursors are compounds of the formula [RuX2(Ar)2]2, where Ar indicates a hexahapto (r ⁇ 6 ) bound benzene or alkyl substituted benzene radical and X indicates halogen, such as fluorine, chlorine, bromine or iodine.
• step ii) is performed at a pH in the range of pH 8 to pH 12.
• step ii) is performed in a liquid phase comprising at least 50 vol.-%, based on the total volume of the reaction mixture, of an inert organic solvent.
• Suitable organic solvents include dichloromethane, ethylenglycol dimethylether, diethylenglycol dimethylether, tetrahydrofurane, acetonitrile, ethylene carbonate, propylene carbonate, dimethyl formamide, dimethylsulfoxide, ethyl acetate, n-propyl acetate, toluene, xylene, heptane, hexane, pentane, N-methyl-2-pyrrolidone, dioxane, 2-methyltetrahydrofurane, methyl-tert. -butyl ether, diisopropyl ether, diethylether, di-n-butyl ether and mixtures thereof.
• the liquid phase may contain water.
• step ii) is performed at a temperature in the range from 10 to 85°C, in particular in the range from 20 to 60°C.
• HZ Br or CI
• excess hydrogen halide HZ will be removed before carrying out the reaction.
• the phosphonium salt (Ilia) can be purified by crystallization and scrubbing, or recrystallization.
• dichloromethane, dichloroethane, chlorobenzene, toluene, heptane, cyclohexane, methylcyclohexane, THF, isopropanol, isobutanol, acetic acid Ci-C4-alkyl ester, acetonitrile or acetone, individually or mixtures thereof, are employed for crystallization or recrystallization.
• EP 490326 in particular to the examples therein.
• reaction of (I) or (VII), respectively, with hydrobromic acid will, as a rule, be carried out using a 10 to 60% by weight strength, in particular 20 to 50% by weight strength, aqueous solution of hydrogen bromide.
• hydrogen bromide is employed in an excess based on the stochiometry, for example in an amount of from 1.5 to 2.5 mols per mole of the compound (I) or (VII), respectively.
• the reaction of (I) or (VII), respectively, with hydrobromic acid is typically carried out at temperatures in the range from -20°C to +25°C, in particular in the range of from -10°C to +10°C.
• the compound of the formula (llld) which is generated during the reaction, may be isolated before it is reacted further, but this will not be necessary in most cases. As already described in scheme 1 , the compound (Ilia) is then reacted with the
• Suitable reaction conditions have been described by E. Widmer et al., Helv. Chim. Acta., 64 (1981 ), 2405-2418 and 2436-2447 and E. Widmer et al., Helv. Chim. Acta., 65 (1982) 671 -685.
• Astacene can be converted to astaxanthin by reduction in accordance with the method described by E.A.H. Hall et al., Chem. Commun. 1978, 387.
• the examples which follow are intended to illustrate the invention in greater detail. The following abbreviations are used: aq. NaOH: 50% b.w. aqueous solution of sodium hydroxide
• a mixture of the base and 31 .4 g of the respective solvent were added into a reaction vessel and heated to the reaction temperature.
• a solution of 10 g (40 mmol) of 6-hydroxy-3-(3-hydroxy-3-methylpent-4-en-1 -ynyl)-2,4,4-trimethylcyclo- hex-2-en-1 -one (compound (II)) in 20 mL of the respective solvent was added within 70 min. with stirring while maintaining the reaction temperature.
• the reaction temperature was maintained for further 30 min. and then the reaction mixture was cooled to 20°C and neutralized with acetic acid to a pH of about pH 6.6.
• Example 20 Reduction of (I) with formic acid in the presence of an achiral catalyst
• the raw product obtained from example 3 was reacted with formic acid by the protocol of example 1 of WO 2016/023772. Thereby, the compound (6R/S)-Hydroxy-3-[(1 E)-3- hydroxy-3-methylpenta-1 ,4-dienyl]-2,4,4-trimethylcyclohex-2-enon-1 -on was obtained in 85% yield.
• Example 21 Reduction of (I) with potassium formiate in the presence of an chiral catalyst

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