WO2018050794A1 - Process for preparing of carotenoid mono-esters - Google Patents

Abstract

The present invention relates to a process for preparing a carotenoid mono-ester of the formula (I), including the stereoisomers of formula (I), wherein, R¹ is e.g. hydrogen, C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₄-C₂₀-alkdienyl, C₆-C₂₀-alktrienyl or C₈-C₂₀-alktetraenyl, R² is e.g. hydrogen or -NR^aR^b, wherein R^a is e.g. hydrogen, C₁-C₄-alkyl, -C(O)-C₁-C₃-alkyl, -Boc or -Cbz, R^b is e.g. hydrogen or C₁-C₄-alkyl, R³ is e.g. hydrogen, X¹, X² are independently from each other CH₂ or C=O, which comprises reacting a phosphonium salt of the formula (II) or a stereoisomer thereof: wherein X¹, R¹, R², and R³ are as defined for formula (I), R⁴ is phenyl, tert-butyl or tolyl, and Y^- is a suitable counteranion, with a 12'-apocarothenal of the formula (III) or a stereoisomer thereof: wherein X² is as defined for formula (I), in the presence of a base or a cryptobase.

Description

Process for preparing of carotenoid mono-esters

The present invention relates to a new process for preparing a carotenoid mono-ester of the formula (I),

wherein R¹, R², R³, X¹ and X² are as defined herein. BACKGROUND OF THE INVENTION

Naturally occurring astaxanthin and zeaxanthin are often present in the form of mono- and diesters of fatty acids. Depending on the source the type of fatty acid and the degree of esterification may vary. For example in the microalgae Haematococcus pluvialis astaxanthin is predominantly present in the form of the mono-esters of palmitic acid, oleic acid linoleic acid or linolenic acid, as described in K. Holtin et al. 2009, Anal. Bioanal. Chem. 395, 1613. The syntheses of astaxanthin mono-esters have been reported, e.g. in US 7,291 ,749, US 7,723,327, EP 1 500 645, and D. Breithaupt et al. 2004, J. Agricult. Food Chem. 52, 3870. All of these syntheses are based on the acylation of the unesterified astaxanthin. However, this approach comes with substantial disadvantages because it virtually always results in the formation of a mixture containing not only the mono-ester but also the di-ester and often some unreacted astaxanthin. Another option known from the art for generating the mono-ester is the partial hydrolysis of astaxanthin di-esters which likewise leads to mixtures of the mono-ester, astaxanthin and often traces of the unreacted di-ester. Hence, in either case elaborate measures are required to isolate the mono-ester from a complex mixture.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a simple and efficient process for preparing a broad spectrum of mono-esters according to formula (I), with the esters being derived from a variety of different acids, including in particular fatty acids and amino acids, the latter being typically N-protected.

It has been found that this object can indeed be achieved by the Wittig reaction between the esterified phosphonium salt of the formula (II) and the unesterified 12'- apocarotenal of the formula (III),

(III) wherein the variables R¹, R², R³, R⁴, Y^", X¹ and X² are as defined herein, in the presence of a base or a cryptobase.

Accordingly, the invention firstly relates to a process for the preparation of a carotenoid mono ester of the formula (I) including the stereoisomers of formula (I), the process comprising the reaction of a phosphonium salt of the formula (II), or a stereoisomer thereof, with a 12'-apocarotenal of the formula (III), or a stereoisomer thereof, in the presence of a base or a cryptobase. This reaction is hereinafter also referred to as "reaction A".

In formulae (I), (II) and (III) the variables X¹, X², R¹, R² and R³ have the following meanings:

X¹, X² are identical or different and selected from the group consisting of Chb and C=0;

R¹ is selected the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C20- alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, C1-C4- alkoxy, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and

alkpentaenyl moieties of the seven aforementioned residues are unsubstituted or may carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH and Ci-C4-alkoxy,

C6-Cio-aryl, benzyl, phenoxy, benzoxy, where the aryl moieties of the four aforementioned residues are unsubstituted or may carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH , Ci-C4-alkyl and C1-C4- alkoxy,

A-COOH , A-CON H2, A-COO-(Ci-C₄-alkyl), and

A-NR^aR^b, R² and R³ are each independently from one another selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, Cs- C2o-alktetraenyl, Cio-C2o-alkpentaenyl, Ci-C4-alkoxy, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the seven aforementioned residues are unsubstituted or may carry 1 , 2 or 3 substituents selected from the group consisting of halogen and Ci-C4-alkoxy,

R² may also be selected from the group consisting of

-COOH, -COO-(Ci-C₄-alkyl), and

-NR^aR^b, or

R¹ and R² together form a group of the formula 1-1 ),

or

R¹, R² and R³ together form a group of the formula (I-2),

* — R

(I-2)

or if R² is -NR^aR^b, R¹ together with R^a may form a C₃-C₄-alkandiyl group, and where, irrespectively of their occurrence,

^* in formulae (1-1 ) and (I-2) indicate the point of attachment to the remainder of the molecule;

R^a is selected from the group consisting of hydrogen, Ci-C₄-alkyl, -C(0)H,

-C(0)-Ci-C3-alkyl, C₄-C7-cycloalkyl, and N-protecting groups such as tert- butyloxycarbonyl (-Boc) and carboxybenzyl (-Cbz),

R^b is selected from the group consisting of hydrogen, Ci-C₄-alkyl,

-C(0)-Ci-C3-alkyl, and N-protecting groups such as -Boc and -Cbz, and

R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl,

C2-Ci9-alkenyl, C₄-Ci9-alkdienyl, C6-Ci9-alktrienyl, Cs-dg-alktetraenyl, Ci-C₄- alkandiyl-COOH, C₂-C₄-alkendiyl-COOH and C₂-C₄-alkyndiyl-COOH,

R^d is hydrogen or Ci-C₄-alkyl, and

A is selected from the group consisting of Ci-Cs-alkandiyl, C2-Cs-alkendiyl and C2- C5-alkyndiyl; In formula (II) the variables R⁴ and Y^" have the following meanings:

R⁴ is selected from the group consisting of phenyl, tert-butyl and tolyl, and

Y^" is selected from the group consisting of halide, sulfate, hydrogensulfate,

mesylate, tosylate, benzenesulfonate, nitrate and Ci-C3-alkyl-carboxylate.

In a further aspect, the invention relates to a process for preparing the phosphonium salt of the formula (II) which comprises the reaction of a compound (IV), or a stereoisomer thereof,

wherein the variables X¹, R⁴ and Y- have the meanings defined herein, with a carboxylic acid or one of its derivatives of the formula (V),

wherein the variables R¹, R² and R³ have the meanings defined herein, and for n = 1 the variable Z is selected from the group consisting of halogen, -OH, -0-C(0)-Ci-C₄-alkyl, and

for n = 2 the variable Z is O or S,

wherein the reaction is carried out in the presence of a tertiary amine and in case a compound of the formula (V) with Z = OH is used also in the presence of an activator. This reaction is hereinafter also referred to as "reaction B". The reaction B is also part of a parallel patent application.

The invention also relates to a process for the preparation of a carotenoid mono ester of the formula (I) including the stereoisomers of formula (I), the process comprising as a first step the preparation of the phosphonium salt of the formula (II), or a

stereoisomer thereof, by the reaction B and then in a second step the reaction of the phosphonium salt of the formula (II), or a stereoisomer thereof, with a

12'-apocarothenal of the formula (III), or a stereoisomer thereof, in the presence of a base or a cryptobase. The invention further relates to phosphonium salts of the formula (II) as defined herein, provided that the group -C(0)CR¹R²R³ is not acetyl, ethoxyacetyl, phenoxyacetyl, propionyl, butyryl, pentanoyl, hexanoyl, palmitoyl, stearoyl or oleoyl. The inventive processes afford an easy and efficient access to carotenoid mono-esters of the formula (I), such as specifically the mono-esters of astaxanthin and zeaxanthin. Particularly, the reaction A of the inventive process averts the disadvantages of the processes of the prior art by largely avoiding the formation of unwanted by-products, such as in particular the carotenoid di-esters and the unesterified carotenoids, which often can only be removed with difficulty and excessive effort.

DETAILED DESCRIPTIOM OF THE INVENTION

In the context of the present invention the terms used generically are defined as follows:

The prefix C_x-C_y denotes the number of possible carbon atoms in the particular case.

The term "halogen" in each case denotes fluorine, bromine, chlorine or iodine, preferably fluorine, chlorine or bromine, and specifically chlorine in the context of Z and bromine in the context of Y-.

The term "Ci-C2o-alkyl" as used herein and in the alkyl moieties of alkoxy and the like refers to saturated straight-chain or branched hydrocarbon radicals having 1 to 3

("Ci-C₃-alkyl"), 1 to 4 ("Ci-C₄-alkyl") or 1 to 20 ("Ci-C₂₀-alkyl") carbon atoms. C1-C3- Alkyl is methyl, ethyl, propyl or isopropyl. Ci-C₄-Alkyl is additionally butyl,

1 - methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1 ,1 -dimethylethyl (tert-butyl). Ci-C2o-Alkyl is additionally also, for example, pentyl, 1 -methylbutyl, 3-methylbutyl,

2.2- dimethylpropyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl,

3.3- dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 -ethyl-1 - methylpropyl, 1 -ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and positional isomers thereof.

The term "C2-C2o-alkenyl" as used herein refers to monounsaturated straight-chain or branched hydrocarbon radicals having 2 to 20 carbon atoms and a double bond in any position, for example ethenyl 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl,

2- butenyl, 3-butenyl, 1 -methyl-1 -propenyl, 2-methyl-1 -propenyl, 1 -methyl-2-propenyl, 2-methyl-2-propenyl, 1 -pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl-1 -butenyl, 3-methyl- 1 -butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methyl-3- butenyl, 1 ,1 -dimethyl-2-propenyl, 1 ,2-dimethyl-1 -propenyl, 1 ,2-dimethyl-2-propenyl,

1 - ethyl-1 -propenyl, 1 -ethyl-2-propenyl, 1 -hexenyl, 3-hexenyl, 5-hexenyl, 1 -methyl-1 - pentenyl, 3-methyl-1 -pentenyl, 2-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1 -methyl-3- pentenyl, 4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1 ,1 -dimethyl-

2- butenyl, 1 ,1 -dimethyl-3-butenyl, 1 ,2-dimethyl-1 -butenyl, 1 ,2-dimethyl-2-butenyl, 1 ,2-dimethyl-3-butenyl, 1 ,3-dimethyl-1 -butenyl, 1 ,3-dimethyl-2-butenyl, 1 ,3-dimethyl-3- butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1 -butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1 -butenyl, 3,3-dimethyl-2-butenyl,

1 - ethyl-1 -butenyl, 1 -ethyl-2-butenyl, 1 -ethyl-3-butenyl, 2-ethyl-1 -butenyl,

2- ethyl-2-butenyl, 2-ethyl-3-butenyl, 1 ,1 ,2-trimethyl-2-propenyl,

1 -ethyl-1 -methyl-2-propenyl, 1 -ethyl-2-methyl-1 -propenyl, 1 -ethyl-2-methyl-2-propenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 1 -heptenyl, 2-heptenyl, 3-heptenyl, 1 -octenyl, 2-octenyl, 3-octenyl, 4-octenyl, as well as linear and branched isomers of nonenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (8Z)-nonenyl, and mixtures thereof, linear and branched isomers of decenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of undecenyl which may differ in the position and configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of dodecenyl which may differ in the position and the

configuration of the double bond and the type of the possible branching, such as (7Z)-dodecenyl, and mixtures thereof, linear and branched isomers of tridecenyl which may differ in the position and configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of tretradecenyl which may differ in the position and configuration of the double bond and the type of the possible branching, such as (7Z)-tretradecenyl and (4Z)-tretradecenyl, and mixtures thereof, linear and branched isomers of pentadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of hexadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (7Z)-hexadecenyl, (7E)-hexadecenyl and

(9E)-hexadecenyl, and mixtures thereof, linear and branched isomers of heptadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of octadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (7Z)-octadecenyl and

(9Z)-octadecenyl, and mixtures thereof, linear and branched isomers of nonadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (9Z)-eicosenyl and (1 1 Z)-eicosenyl, and mixtures thereof.

The term "C4-C2o-alkdienyl" as used herein refers to diunsaturated straight-chain or branched hydrocarbon radicals having 4 to 20 carbon atoms and two double bonds in any positions, provided that the two double bounds are either conjugated or isolated, for example 1 ,3-butadienyl, 1 ,3-pentadienyl, 2,4-pentadienyl, 1 ,4-pentadienyl,

1 ,3-hexadienyl, 1 ,4-hexadienyl, 1 ,5-hexadienyl, 2,4-hexadienyl, 2,5-hexadienyl,

1 .3- heptadienyl, 1 ,4-heptadienyl, 1 ,5-heptadienyl, 1 ,6-heptadienyl, 2,4-heptadienyl, 2,5-heptadienyl, 2,6-heptadienyl, 3,5-heptadienyl, 3,6-heptadienyl, 1 ,3-octadienyl,

1 .5- octadienyl, 1 ,7-octadienyl, 2,4-octadienyl, 2,6-octadienyl, 3,5-octadienyl,

3,7-octadienyl, 4,6-octadienyl, 5,7-octadienyl, 1 ,3-nonadienyl, 1 ,4-nonadienyl,

1 .6- nonadienyl, 1 ,8-nonadienyl, 2,4-nonadienyl, 2,7-nonadienyl, 3,5-nonadienyl, 4,6-nonadienyl, 5,7-nonadienyl, 6,8-nonadienyl, 1 ,3-decadienyl, 1 ,6-decadienyl,

2.4- decadienyl, 2,8-decadienyl, 3,5-decadienyl, 4,6-decadienyl, 5,7-decadienyl, 6,8-decadienyl, 7,9-decadienyl, 1 ,3-undecadienyl, 1 ,8-undecadienyl, 2,4-undecadienyl, 2,9-undecadienyl, 3,5-undecadienyl, 4,6-undecadienyl, 5,7-undecadienyl,

5.10- undecadienyl, 6,8-undecadienyl, 7,9-undecadienyl, 8,10-undecadienyl,

1 ,3-dodecadienyl, 1 ,8-dodecadienyl, 2,4-dodecadienyl, 2,7-dodecadienyl,

3.5- dodecadienyl, 4,6-dodecadienyl, 5,7-dodecadienyl, 5,1 1 -dodecadienyl,

6.8- dodecadienyl, 7,9-dodecadienyl, 8,10-dodecadienyl, 9,1 1 -dodecadienyl,

1 ,3-tridecadienyl, 1 ,8-tridecadienyl, 2,4-tridecadienyl, 3,5-tridecadienyl,

4.6- tridecadienyl, 5,7-tridecadienyl, 5,1 1 -tridecadienyl, 6,8-tridecadienyl,

7.9- tridecadienyl, 8,10-tridecadienyl, 9,1 1 -tridecadienyl, 10,12-tridecadienyl,

I , 3-tetradecadienyl, 1 ,9-tetradecadienyl, 2,4-tetradecadienyl, 3,5-tetradecadienyl, 4,6-tetradecadienyl, 5,7-tetradecadienyl, 5,1 1 -tetradecadienyl, 6,8-tetradecadienyl, 7,9-tetradecadienyl, 8,10-tetradecadienyl, 9,1 1 -tetradecadienyl, 10,12-tetradecadienyl,

I I , 13-tetradecadienyl, 1 ,3-pentadecadienyl, 1 ,9-pentadecadienyl, 2,4-pentadecadienyl, 3,5-pentadecadienyl, 4,6-pentadecadienyl, 5,7-pentadecadienyl, 5,12-pentadecadienyl, 6,8-pentadecadienyl, 7,9-pentadecadienyl, 8,10-pentadecadienyl,

9.1 1 - pentadecadienyl, 10,12-pentadecadienyl, 1 1 ,13-pentadecadienyl,

12,14-pentadecadienyl, as well as linear and branched isomers of hexadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as (7Z,10Z)-hexadecadienyl and

(7E,10E)-hexadecadienyl, and mixtures thereof, linear and branched isomers of heptadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of octadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of nonadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof. The term "C6-C2o-alktrienyl" as used herein refers to triunsaturated straight-chain or branched hydrocarbon radicals having 6 to 20 carbon atoms and three double bonds in any positions, provided that the each pair out of the three double bounds is either conjugated or isolated, for example 1 ,3,5-hexatrienyl, 1 ,3,5-heptatrienyl,

1 ,4,6-heptatrienyl, 1 ,3,6-heptatrienyl, 2,4,6-heptatrienyl, 1 ,3,5-octatrienyl,

1 ,3,6-octatrienyl, 1 ,3,7-octatrienyl, 1 ,4,6-octatrienyl, 1 ,4,7-octatrienyl, 1 ,5,7-octatrienyl, 2,4,6-octatrienyl, 2,4,7-octatrienyl, 2,5,7-octatrienyl, 3,5,7-octatrienyl, 1 ,3,5-nonatrienyl, 1 ,3,8-nonatrienyl, 2,4,6-nonatrienyl, 2,4,7-nonatrienyl, 3,5,7-nonatrienyl,

4,6,8-nonatrienyl, 1 ,4,7-nonatrienyl, 1 ,3,5-decatrienyl, 1 ,3,8-decatrienyl,

2.4.6- decatrienyl, 2,4,9-decatrienyl, 3,5,7-decatrienyl, 4,6,8-decatrienyl,

5,7,9-decatrienyl, 2,5,7-decatrienyl, 1 ,6,8-decatrienyl, 2,7,9-decatrienyl,

1 .4.7- decatrienyl, 2,5,9-decatrienyl, 1 ,3,5-undecatrienyl, 1 ,3,8-undecatrienyl,

1 .6.8- undecatrienyl, 2,4,6-undecatrienyl, 2,4,10-undecatrienyl, 2,6,9-undecatrienyl,

2.7.9- undecatrienyl, 3,5,7-undecatrienyl, 4,6,8-undecatrienyl, 4,7,10-undecatrienyl,

5.7.9- undecatrienyl, 6,8,10-undecatrienyl, 1 ,3,5-dodecatrienyl, 1 ,3,8-dodecatrienyl, 1 ,6,8-dodecatrienyl, 2,4,6-dodecatrienyl, 2,4,10-dodecatrienyl, 2,6,9-dodecatrienyl,

3,5,7-dodecatrienyl, 4,6,8-dodecatrienyl, 4,7,1 1 -dodecatrienyl, 5,7,9-dodecatrienyl,

6.8.10- dodecatrienyl, 7,9,1 1 -dodecatrienyl, 1 ,3,5-tridecatrienyl, 1 ,3,7-tridecatrienyl, 1 ,8,10-tridecatrienyl, 2,4,6-tridecatrienyl, 2,4,10-tridecatrienyl, 2,7,10-tridecatrienyl, 3,5,7-tridecatrienyl, 4,6,8-tridecatrienyl, 4,7,1 1 -tridecatrienyl, 5,7,9-tridecatrienyl, 6,8,10-tridecatrienyl, 7,9,1 1 -tridecatrienyl, 8,10,12-tridecatrienyl, 1 ,3,5-tetradecatrienyl,

1 .3.9- tetradecatrienyl, 2,4,6-tetradecatrienyl, 2,4,10-tetradecatrienyl,

2.7.10- tetradecatrienyl, 3,5,7-tetradecatrienyl, 4,6,8-tetradecatrienyl,

4.7.1 1 - tetradecatrienyl, 5,7,9-tetradecatrienyl, 6,8,10-tetradecatrienyl,

7,9,1 1 -tetradecatrienyl, 7,10,12-tetradecatrienyl, 8,10,12-tetradecatrienyl,

9,1 1 ,13-tetradecatrienyl, 1 ,3,5-pentadecatrienyl, 1 ,3,1 1 -pentadecatrienyl,

2.4.6- pentadecatrienyl, 2,4,9-pentadecatrienyl, 2,9,12-pentadecatrienyl,

3.5.7- pentadecatrienyl, 4,6,8-pentadecatrienyl, 4,7,10-pentadecatrienyl,

5,7,9-pentadecatrienyl, 6,8,10-pentadecatrienyl, 7,9,1 1 -pentadecatrienyl,

7,10,12-pentadecatrienyl, 8,10,12-pentadecatrienyl, 9,1 1 ,13-pentadecatrienyl, 10,12,14-pentadecatrienyl, as well as linear and branched isomers of hexadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as (7Z,10Z,13Z)-hexadecatrienyl,

(4Z,7Z,10Z)-hexadecatrienyl, (6E,8E,10Z)-hexadecatrienyl,

(7Z,9E,1 1 Z)-hexadecatrienyl, (7Z,9E,1 1 E)-hexadecatrienyl and

(7E,9E,1 1 E)-hexadecatrienyl, and mixtures thereof, linear and branched isomers of heptadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of octadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of nonadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof.

The term "C8-C2o-alktetraenyl" as used herein refers to tetraunsaturated straight-chain or branched hydrocarbon radicals having 8 to 20 carbon atoms and four double bonds in any positions, provided that the each pair out of the four double bounds is either conjugated or isolated, for example 1 ,3,5,7-octatetraenyl, 1 ,3,5,7-nonatetraenyl, 1 ,3,5,8-nonatetraenyl, 2,4,6,8-nonatetraenyl, 1 ,4,6,8-nonatetraenyl,

1 ,3,6,8-nonatetraenyl, 1 ,3,5,7-decatetraenyl, 1 ,3,5,9-decatetraenyl,

2.4.6.8- decatetraenyl, 2,4,7,9-decatetraenyl, 3,5,7,9-decatetraenyl,

1 ,3,5,7-undecatetraenyl, 1 ,3,8,10-undecatetraenyl, 2,4,6,8-undecatetraenyl,

2,4,7,10-undecatetraenyl, 3,5,7,9-undecatetraenyl, 4,6,8, 10-undecatetraenyl,

1 ,3,5,7-dodecatetraenyl, 1 ,3,6,8-dodecatetraenyl, 2,4,6,8-dodecatetraenyl,

2.5.8.10- dodecatetraenyl, 3,5,7,9-dodecatetraenyl, 4,6,8, 10-dodecatetraenyl,

4.6.9.1 1 - dodecatetraenyl, 5,7,9,1 1 -dodecatetraenyl, 1 ,3,5,7-tridecatetraenyl,

1 .3.8.10- tridecatetraenyl, 2,4,6,8-tridecatetraenyl, 2,5,8,1 1 -tridecatetraenyl,

3,5,7,9-tridecatetraenyl, 3,5,8,1 1 -tridecatetraenyl, 4,6,8,10-tridecatetraenyl,

5.7.9.1 1 - tridecatetraenyl, 6,8,10,12-tridecatetraenyl, 1 ,3,5,7-tetradecatetraenyl,

1 ,3,9,1 1 -tetradecatetraenyl, 2,4,6,8-tetradecatetraenyl, 2,5,8,1 1 -tetradecatetraenyl,

3.5.7.9- tetradecatetraenyl, 3,5,9,12-tetradecatetraenyl, 4,6,8, 10-tetradecatetraenyl, 5,7,9,1 1 -tetradecatetraenyl, 6,8,10,12-tetradecatetraenyl, 7,9,1 1 ,13-tetradecatetraenyl, 1 ,3,5,7-pentadecatetraenyl, 1 ,4,10,13-pentadecatetraenyl, 2,4,6,8-pentadecatetraenyl, 2,4,9,1 1 -pentadecatetraenyl, 3,5,7,9-pentadecatetraenyl, 3,5,8,1 1 -pentadecatetraenyl,

4.6.8.10- pentadecatetraenyl, 5,7,9,1 1 -pentadecatetraenyl,

6,8,10,12-pentadecatetraenyl, 7,9,1 1 ,13-pentadecatetraenyl,

8,10,12,14-pentadecatetraenyl, 1 ,3,5,7-hexadecatetraenyl, 2,4,6,8-hexadecatetraenyl, 2,6,9,12-hexadecatetraenyl, 3,5,7,9-hexadecatetraenyl, 4,6,8, 10-hexadecatetraenyl, 5,7,9,1 1 -hexadecatetraenyl, 6,8, 10,12-hexadecatetraenyl,

6,8,1 1 ,14-hexadecatetraenyl, 7,9,1 1 ,13-hexadecatetraenyl,

8,10,12,14-hexadecatetraenyl, 8,10,13,15-hexadecatetraenyl,

9,1 1 ,13,15-hexadecatetraenyl, 1 ,3,5,7-heptadecatetraenyl, 2,4,6,8-heptadecatetraenyl, 3,5,7,9-heptadecatetraenyl, 4,6,8,10-heptadecatetraenyl,

4,7,10,13-heptadecatetraenyl, 5,7,9,1 1 -heptadecatetraenyl,

6.8.10.12- heptadecatetraenyl, 6,8,1 1 ,14-heptadecatetraenyl,

7.9.1 1 .13- heptadecatetraenyl, 7,9,12,14-heptadecatetraenyl,

8,10,12,14-heptadecatetraenyl, 9,1 1 ,13,15-heptadecatetraenyl,

10,12,14,16-heptadecatetraenyl, as well as linear and branched isomers of

octadecatetraenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as

(3Z,6Z,9Z,12Z)-octadecatetraenyl, and mixtures thereof, linear and branched isomers of nonadecatetraenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosatetraenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof.

The term "Cio-C2o-alkpentaenyl" as used herein refers to pentaunsaturated straight- chain or branched hydrocarbon radicals having 10 to 20 carbon atoms and five double bonds in any positions, provided that the each pair out of the five double bounds is either conjugated or isolated, for example 1 ,3,5,7,9-decapentaenyl,

1 ,3,5,7,9-undecapentaenyl, 1 ,3,6,8,10-undecapentaenyl, 1 ,4,6,8,10-undecapentaenyl,

2.4.6.8.10- undecapentaenyl, 1 ,3,5,7,9-dodecapentaenyl, 1 ,3,6,8,10-dodecapentaenyl,

1 .4.6.9.1 1 - dodecapentaenyl, 2,4,6,8,10-dodecapentaenyl, 3,5,7,9,1 1 -dodecapentaenyl,

1 .3.5.7.9- tridecapentaenyl, 1 ,4,7, 0, 2-tridecapentaenyl, 2,4,6,8, 0-tridecapentaenyl, 2,5,7,9,1 1 -tridecapentaenyl, 3,5,7,9,1 1 -tridecapentaenyl, 4,6,8,10,12-tridecapentaenyl, 1 ,3,5,7,9-tetradecapentaenyl, 1 ,4,7, 10,13-tetradecapentaenyl,

2.4.6.8.10- tetradecapentaenyl, 2,5,8,1 1 ,13-tetradecapentaenyl,

3.5.7.9.1 1 - tetradecapentaenyl, 3,5,8, 10,12-tetradecapentaenyl,

4.6.8.10.12- tetradecapentaenyl, 4,6,8, 10,13-tetradecapentaenyl,

5.7.9.1 1 .13- tetradecapentaenyl, 1 ,3,5,7,9-pentadecapentaenyl,

2,4,6,8, 10-pentadecapentaenyl, 2,5,8,11 ,14-pentadecapentaenyl,

3,5,7,9,1 1 -pentadecapentaenyl, 3,5,8,1 1 ,14-pentadecapentaenyl,

4,6,8,10,12-pentadecapentaenyl, 4,6,8,1 1 ,14-pentadecapentaenyl,

5.7.9.1 1.14- pentadecapentaenyl, 5,7,9,12,14-pentadecapentaenyl,

6,8,10,12,14-pentadecapentaenyl, 1 ,3,5,7,9-hexadecapentaenyl, 2.4.6.8.10- hexadecapentaenyl, 2,5,8,1 1 ,14-hexadecapentaenyl,

3.5.7.9.1 1 - hexadecapentaenyl, 3,5,8,10,12-hexadecapentaenyl,

4.6.8.10.12- hexadecapentaenyl, 5,7,9,1 1 ,13-hexadecapentaenyl,

6.8.10.12.14- hexadecapentaenyl, 7,9,1 1 ,13,15-hexadecapentaenyl,

1 ,3,5,7, 9-heptadecapentaenyl, 1 ,3,6,9,1 1 -heptadecapentaenyl,

2.4.6.8.10- heptadecapentaenyl, 2,4,7, 10,14-heptadecapentaenyl,

3.5.7.9.1 1 - heptadecapentaenyl, 4,6,8, 10,12-heptadecapentaenyl,

5.7.9.1 1.13- heptadecapentaenyl, 6,8,10,12,14-heptadecapentaenyl,

6.8.1 1 .13.15- heptadecapentaenyl, 7,9,1 1 ,13,15-heptadecapentaenyl,

8,10,12,14,16-heptadecapentaenyl, as well as linear and branched isomers of octadecapentaenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as

(3Z,6Z,9Z,12Z,15Z)-octadecapentaenyl, and mixtures thereof, linear and branched isomers of nonadecapentaenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosapentaenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as (5Z,8Z,1 1 Z,14Z,17Z)-eicosapentaenyl and mixtures thereof. The term "Ci-C4-alkoxy" denotes straight-chain or branched saturated alkyl groups comprising 1 to 4 carbon atoms which are bonded via an oxygen atom. Examples of Ci-C4-alkoxy are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, 1 -methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) and 1 ,1 -dimethylethoxy (tert-butoxy).

The term "C6-Cio-aryl" is understood as an unsaturated mono- or dicyclic hydrocarbon group having at least one benzene ring; examples include phenyl, indanyl and naphthyl. The term "-COO-(Ci-C4-alkyl)" refers to a Ci-C4-alkoxy group, as defined above, which is bound to the remainder of the molecule via a carbonyl group. Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,

butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl. The term "-C(0)-Ci-C3-alkyl" refers to a Ci-C3-alkyl group, as defined above, which is bound to the remainder of the molecule via a carbonyl group. Examples are methylcarbonyl, ethylcarbonyl, propylcarbonyl and isopropylcarbonyl.

The term "C4-C7-cycloalkyl" denotes a cyclic, saturated hydrocarbyl radical comprising 4 to 7 carbon atoms. Examples are cyclobutyl, cyclopentyl, cyclohexyl,

bicyclo[2.1 .1]hexyl, cycloheptyl, bicyclo[2.2.1 ]heptyl, bicyclo[3.1 .1]heptyl and bicyclo[2.2.1 ]heptyl. The term "d-Cs-alkandiyl" denotes a straight-chain or branched hydrocarbon diradical having 1 to 5 carbon atoms, such as methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl, 2-methylpropan-1 ,3-diyl, butan-1 ,3-diyl, butan-1 ,4-diyl, 2-methylbutan-1 ,4-diyl and pentan-1 ,5-diyl. The term "C2-C5-alkendiyl" denotes a straight-chain or branched unsaturated hydrocarbon diradical having 2 to 5 carbon atoms, such as ethen-1 ,2-diyl, prop-1 -en- 1 ,3-diyl, but-2-en-1 ,4-diyl but-1 -en-1 ,3-diyl and pent-2-en-1 ,5-diyl.

The term "C2-C5-alkyndiyl" denotes a straight-chain or branched hydrocarbon diradical which has 2 to 5 carbon atoms and includes a triple bond, such as ethyn-1 ,2-diyl, prop-1 -yn-1 ,3-diyl, but-2-yn-1 ,4-diyl and pent-2-yn-1 ,5-diyl.

The term "N-protecting group" denotes a protective group suitable for protecting or blocking amino groups. With regard to N-protective groups reference is made to P.G.M. Wuts, "Greene's Protective Groups in Organic Synthesis", 5^th ed. John Wiley and Sons, 2014, Chapter 7, pages 895 - 1 194 and the references cited therein. N-protecting groups are in particular protecting groups, which together with the nitrogen atom form carbamate type group, such as 9-fluorenylmethyl carbamate (Fmoc), substituted 9-fluorenylmethyl carbamates such as Bts-Fmoc, Dtb-Fmoc, Mio-Fmoc, Dio-Fmoc, and 9-(2,7-dibromo)fluorenylmethyl carbamate, 3-idenylmethyl carbamates such as

2-chloro-3-indenylmethyl carbamate (Climoc) and Benz[f]inden-3-ylmethyl (Bimoc), 1 ,1 -dioxobenzo[b]thiophene-2-ylmethyl carbamate (Bsmoc), substituted ethyl carbamates such as 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate, (Teoc), (2-phenyl-2-trimethylsilyl)ethyl carbamate (Psoc), 2-chloroethyl carbamate, 2-phenylethyl carbamate (hZ), 1 ,1 -dimethyl-2,2-dibromoethyl carbamate (DB-t-Boc), 1 ,1 -dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 2-pyridylethyl carbamate (Pyoc), t-butyl carbamate (BOC), fluorous BOC (^FBOC), 1 - and 2-adamantyl carbamate (Adoc and 2-Adoc), 1 -(1 -adamantyl)-1 -methylethyl carbamate (Adpoc), 1 -(3,5-di-t-butylphenyl)-1 -methylethyl carbamate (t-Bumeoc), N-(2-pivaloylamino)- 1 ,1 -dimethylethyl carbamate, allyl carbamate (Alloc), benzyl carbamate (Cbz or Z), and substituted benzyl carbamates, such as 4-methoxybenzyl carbamate (Moz),

4-nitrobenzyl carbamate (PNZ), 4-methylsulfinylbenzyl carbamate (Msz),

4-trifluoromethylbenzyl carbamate (CTFB), and 2-naphtylmethyl carbamate (CNAP). Preference is given to Cbz and BOC. The remarks made below concerning preferred embodiments of the processes of the invention, the reaction conditions and also of compounds of formulae (I), (II), (III), (IV) and (V) involved in the processes, especially with respect to their substituents R¹, R², R³, R⁴, X¹, X², Y-' Z, A, R^a, R^b, R^c and R^d, are valid both on their own and, in particular, in every possible combination with each other.

In the context of formulae (I), (II), (III) and (IV) the term "stereoisomer" relates in particular to the configuration of the exocyclic double bonds, which may independently from each other have E or Z configuration. In the formulae (I), (II), (III) and (IV) only the all-E isomers are shown. However, it will be possible that one or more of the double bonds have Z configuration, which is not depicted in the formulae. In the context of formulae (I), (II), (III) and (IV) the term "stereoisomer" also relates to the configuration of the ring carbon atom adjacent to X¹ or X², respectively, which bears the OH group or the group 0-CO)CR¹R²R³, respectively, which may have S-configuration or

R-configuration.

As stated above C-C double bonds in the exocyclic chains of the compounds of formulae (I), (II), (III) and (IV) may independently from each other have E or Z configuration. According to preferred groups of embodiments of the present invention the exocyclic C-C double bonds in the compounds of formulae (I), (II), (III) and (IV) are predominantly, or in particular completely, in the E configuration.

When performing the reaction A of the invention the configurations of the exocyclic C-C double bonds of the compounds (II) and (III) remain essentially unchanged, i.e. the configurations of the exocyclic double bonds in the product of the formula (I) are essentially identical to the respective ones in the educts of the formulae (II) and (III).

Thus, the configurations of the exocyclic double bonds of the product of formula (I) are identical with the configurations of the corresponding exocyclic C-C double bonds of the educts of formulae (II) and (Mil) to a degree of typically at least 70 mol-%, preferably at least 80 mol-%, in particular at least 90 mol-% and specifically at least

98 mol-%.

Moreover, the newly formed exocyclic double bond of the compound of formula (I), i.e. the double bond in position 1 1 or 1 1 ' of the octadecanonaendiyl moiety of compound (I) (see below), frequently has predominantly E-configuration. In this context, the term "predominantly E configuration" means that said double bond in position 1 1 or 1 1 ' adopts E-configuration to a degree of more than 50%, preferably at least 80% in particular at least 90% and in especially at least 95%.

(I)

In particular, educts of formula (II) are used in reaction A, wherein both exocyclic C-C double bonds essentially have E configuration, i.e. at least 80 mol-%, in particular at least 90 mol-% and especially at least 95 mol-% of the educt (II) has all-E

configuration. In particular, educts of formula (III) are used in reaction A, wherein the six exocyclic C-C double bonds essentially have E configuration, i.e. at least 80 mol-%, in particular at least 90 mol-% and especially at least 95 mol-% of the educt (III) has all- E configuration. In particular using educts of formulae (II) and (III) in reaction A, which both essentially have all-E configuration, will yield a product of formula (I) wherein all nine exocyclic C-C double bonds essentially have E configuration, i.e. at least 80 mol- %, in particular at least 90 mol-% and especially at least 95 mol-% of the product have an all-E configuration.

The compounds of the formulae (II), (III) and (IV) each have an asymmetric center in position 3 of the 6-membered cycle and can therefore exist as an enantiomeric mixture of the 3R and 3S isomers, e.g. as a racemate, or in the form of the pure isomers having the formulae (Ma), (Ilia), (IVa), (lib), (1Mb) and (IVb), respectively:

In a preferred embodiment of the invention the compounds of formulae (II), (III) and (IV), with X¹ and X² both being C=0, are predominantly, i.e. to an extent of at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-%, present as their S isomers (I la), (Ilia) or (IVa). Likewise, according to a further preferred embodiment the compounds of formulae (II), (III) and (IV), with X¹ and X² both being CH2, are predominantly, i.e. to an extent of at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-%, present as their R isomers lla), (Ilia) or (IVa).

Likewise, the compound of the formula (I) has two asymmetric centers in positions 3 and 3' of its two 6-membered cycles and can therefore exist as a diasteromeric mixture of the (3R,3'R)-isomer, the (3R,3'S)-isomer, the (3S,3'R)-isomer and the

(3S,3'S)-isomers, as a enantiomeric mixture of either its (3R,3'S)- and (3S,3'R)-isomers or its (3R,3'R)- and (3S,3'S)-isomers, or in the form of the pure isomers having the formulae (la), (lb), (lc) and (Id), respectively:

In a preferred embodiment of the invention the compound of formula (I) with X¹ and X² both being C=0 is predominantly, i.e. to an extent of at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-%, present as its S,S' isomer (la). Likewise, according to a further preferred embodiment the compound of formula (I) with X¹ and X² both being Chb is predominantly, i.e. to an extent of at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-%, present as its R,R' isomer (la).

Preferably, the variables R¹, R², R³ in the compounds of formulae (I), (II) and (V) have the following meanings:

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, A-COOH , A-CON H2 and A-COO-(Ci-C₄-alkyl) and Ci-C₄-alkoxy, in particular hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C₄-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C20- alktetraenyl, Cio-C₂₀-alkpentaenyl, A-COOH, A-CON H2 and A-COO-(Ci-C₄-alkyl) and specifically Ci-C2o-alkyl, C2-C2o-alkenyl, C₄-C2o-alkdienyl, C6-C2o-alktrienyl, C₈-C₂o-alktetraenyl, A-COOH, A-CON H2 and A-COO-(Ci-C₄-alkyl),

where A, at each occurrence, is as defined above and in particular C1-C4- alkandiyl and especially CH2 or CH2CH2,

R² is selected from the group consisting of hydrogen, -COOH, -COO-(Ci-C₄-alkyl), and -NR^aR^b, where R^a and R^b have the meanings defined above, in particular R² is hydrogen or -NR^aR^b, where R^a and R^b have the meanings defined above and specifically have the following meanings:

R^a is selected from the group consisting of hydrogen, Ci-C₄-alkyl, -C(0)-Ci-C3- alkyl, and N-protecting groups, in particular -Boc or -Cbz, and

R^b is hydrogen or Ci-C₄-alkyl, or, alternatively,

R¹ and R² together may form a group of formulae (1-1 ) or (I-2), in particular may form a group of formula (1-1 ) only, and specifically do not form a group of formulae (1-1 ) or (I-2). In this context the variables in R^c and R^d are as defined above and in particular have the following meanings:

R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl, C2-C19- alkenyl, C4-Ci9-alkdienyl, C6-Ci9-alktrienyl and Cs-dg-alktetraenyl, in particular hydrogen, Ci-Cig-alkyl, C2-Cig-alkenyl, C4-Cig-alkdienyl and

C6-Ci9-alktrienyl and specifically hydrogen, Ci-Ci7-alkyl, C2-Ci7-alkenyl and C4-Ci7-alkdienyl, and

R^d is hydrogen or Ci-C4-alkyl and in particular hydrogen,

R³ is selected from the group consisting of hydrogen, Ci-C2o-alkyl and C2-C20- alkenyl, and in particular is hydrogen.

More preferably, the variables R¹, R², R³ in the compounds of formulae (I), (II) and (V) have the following meanings:

R¹ is selected from the group consisting of hydrogen, Ci-Cis-alkyl, C2-Ci8-alkenyl, C₄-Ci8-alkdienyl, C₆-Ci₈-alktrienyl, C₈-Ci₈-alktetraenyl, A-COOH, A-CONH2 and A-COO-(Ci-C4-alkyl) and in particular hydrogen, Ci-Cis-alkyl, C2-Ci8-alkenyl, C₄-Ci8-alkdienyl, C₆-Ci₈-alktrienyl, A-COOH, A-CONH2 and A-COO-(Ci-C₄-alkyl), where A, at each occurrence, is as defined above and in particular C1-C4- alkandiyl and especially CH2 or CH2CH2,

R² is hydrogen or -NR^aR^b, where R^a and R^b have the meanings defined above and in particular have the following meanings:

R^a is selected from the group consisting of hydrogen, Ci-C4-alkyl, -C(0)-Ci-C3- alkyl and N-protecting groups such as -Boc and -Cbz, specifically hydrogen, -Boc and -Cbz, and

R^b is hydrogen or Ci-C4-alkyl, specifically hydrogen, and

R³ is hydrogen or Ci-C2o-alkyl, in particular hydrogen.

Preferably, the variables X¹ and X² in the compounds of formulae (I), (II), (III) and (IV) independently of each other are either CH2 or C=0, in particular are both either CH2 or C=0, and specifically are both C=0.

Preferably, the variables R⁴ and Y- in the compounds of formulae (II) and (IV) have the following meanings:

R⁴ is selected from the group consisting of phenyl, tert-butyl and tolyl, and in

particular is phenyl, and

Y^" is selected from the group consisting of halide, such as bromide or chloride, sulfate, hydrogensulfate, mesylate and tosylate, in particular bromide, chloride, sulfate and hydrogensulfate, and specifically is bromide. Preferably, the variable Z in the compound of formula (V) is, in case n = 1 , chlorine, -OH or -0-C(0)-CH3, in particular chlorine or -OH, and, in case n = 2, is O.

Preferably, in the process of the invention, any group NR^aR^b in the compounds of formulae (II) and (V) is a tertiary amino group or at least one radical R^a or R^b is an N-protecting group, which can be cleaved from the compound of formula (I) after the reaction of the compound of formula (II) with the compound of formula (III) or from compound (II) after the reaction of the compound of formula (IV) with the compound of formula (V).

According to a first preferred group of embodiments of the invention the group

-C(0)CR¹R²R³ in formulae (I), (II) and (V) is derived from a saturated or unsaturated fatty acid, having 2 to 22 carbon atoms, in particular 10 to 20 carbon atoms i.e. R² and R³ are H and R¹ is selected from hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C20- alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, in particular from Ci-Ci8-alkyl, C2-Ci8-alkenyl, C4-Ci8-alkdienyl, C6-Ci8-alktrienyl and Cs-ds-alktetraenyl and especially from hydrogen, C6-Ci8-alkyl, C6-Ci8-alkenyl, C6-Cis-alkdienyl and C6-C18- alktrienyl. Examples of such groups -C(0)CR¹R²R³ include but are not limited to acetyl, caproyl, lauroyl, myristoyl, palmitoyl, stearoyl, myristoleoyl, palmitoleoyl, oleoyl, linoleoyl, a-linolenoyl, γ-linolenoyl, and arachidonoyl, in particular acetyl, lauroyl, myristoyl, palmitoyl, oleoyl, linoleoyl, a-linolenoyl, γ-linolenoyl, arachidonoyl, and specifically acetyl, lauroyl, myristoyl, palmitoyl, oleoyl, linoleoyl, a-linolenoyl, γ-linolenoyl. In this particular group of embodiments, the variables X¹ and X² in formulae (I) and (II) are both especially C=0.

According to a second group of embodiments of the invention the group -C(0)CR¹R²R³ in formulae (I), (II) and (V) is derived from an a-amino acid or an N-protected a-amino acid, i.e. R² is a radical NR^aR^b, where R^a and R^b are as defined above and where in particular one or both of R^a and R^b are an N-protecting groups such as BOC or Cbz, respectively, while the other group R^a and R^b is hydrogen, Ci-C4-alkyl,

-C(0)H, -C(0)-Ci-C3-alkyl or C4-C7-cycloalkyl, in particular hydrogen or Ci-C4-alkyl, or R^a together with R¹ may form a C3-C4-alkandiyl group. In this group of embodiments, R³ is in particular hydrogen. R¹ is as defined above and in particular selected from hydrogen, Ci-C4-alkyl, which is unsubstituted or carries one OH group, A-CO2H , A-CON H2, where A is as defined above and in particular CH2 or CH2CH2, and benzyl, which is unsubstituted or carries OH. Examples of such groups -C(0)CR¹R²R³ include but are not limited to N-Boc-glycyl, N-Cbz-glycyl, sarconsinyl, N-Boc-sarcosinyl, N-Cbz- sarcosinyl, prolinyl, N-Boc-prolinyl, N-Cbz-prolinyl, N-Boc-alaninyl, N-Cbz-alaninyl, N-Boc-valinyl, N-Cbz-valinyl, N-Boc-leucinyl, N-Cbz-leucinyl, N-Boc-isoleucinyl, N-Cbz- isoleucinyl, N-Boc-phenylalaninyl, N-Cbz-phenylalaninyl, N-Boc-tyrosinyl, N-Cbz- tyrosinyl, N-Boc-serinyl, N-Cbz-serinyl, N-Boc-threoninyl, N-Cbz-threoninyl, N-Boc- asparaginyl, N-Cbz-asparaginyl, N-Boc-glutaminyl, N-Cbz-glutaminyl, in particular N-Boc-glycyl, N-Cbz-glycyl, N-Boc-alaninyl, N-Cbz-alaninyl, N-Boc-valinyl, N-Cbz- valinyl, N-Boc-leucinyl, N-Cbz-leucinyl, N-Boc-isoleucinyl, N-Cbz-isoleucinyl, N-Boc- sarcosinyl, N-Cbz-sarcosinyl, N-Boc-prolinyl, N-Cbz-prolinyl, and specifically N-Boc- glycyl and N-Boc-sarcosinyl, and also the corresponding deprotected radicals. In this particular group of embodiments, the variables X¹ and X² in formulae (I) and (II) are both especially C=0.

According to a third preferred group of embodiments of the invention the group -C(0)CR¹R²R³ in formulae (I), (II) and (V) is derived from a saturated or unsaturated dicarboxylic acid or a semi-ester thereof. In this group of embodiments, R² and R³ are H and R¹ is a group A-COOH or A-COO-Ci-C4-alkyl, where A is as defined above and in particular Chb or CH2CH2. Examples of such groups -C(0)CR¹R²R³ include, but are not limited to, succinoyl, i.e. -C(=0)-CH2CH2COOH, and the corresponding Ci-C4-alkyl esters -C(=0)-CH2CH2COO-Ci-C4-alkyl. In this particular group of embodiments, the variable X¹ in in formula (II), and also the variable X¹ and X² in formula (I) are especially C=0.

Accordingly, the carboxylic acid or one of its derivatives of the formula (V) is preferably selected from the group consisting of:

- saturated and unsaturated fatty acids having 8 to 20 C-atoms, in particular having 12 to 20 C-atoms, and the acid halides, such as in particular the acid chlorides, derived therefrom,

- acetyl chloride, acetic anhydride,

- succinic acid, succinic acid anhydride, and

- N-Boc or N-Cbz protected a-amino acids preferably selected from glycine, alanine, valine, leucine, isoleucine, sarcosine and proline.

The reactions of the invention as described hereinafter are performed in reaction vessels customary for such reactions, the reaction being carried out in a continuous, semicontinuous or batchwise manner. In general, the particular reactions will be carried out under atmospheric pressure. The reactions may, however, also be carried out under reduced or elevated pressure.

The reaction A of the inventive process for preparing a carotenoid mono ester of the formula (I) may be considered to be a Wittig reaction. The conversion is effected by reacting a phosphonium salt of the formula (II) with a 12'-apocarotenal of the formula (III) in the presence of a base or a cryptobase.

In one embodiment of the invention the reaction A is carried out in the presence of a base.

In another embodiment of the invention the reaction A is carried out in the presence of a cryptobase. Suitable bases for the reaction A of the inventive process are for example alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate or calcium carbonate, alkali metal bicarbonates, such as sodium bicarbonate, alcoholates, such as in particular alkali metal C1-C5-alkanolat.es, e.g. sodium methanolate, sodium ethanolate, sodium isopropanolate, sodium tert.-butylate, potassium methanolate, potassium ethanolate, potassium isopropanolate or potassium tert.-butylate, and amine bases, which are preferably selected from tertiary amines of the formula (A): N R^eR^fR9 (A), wherein the groups R^e, R^f and Rs are each independently from one another 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^e and R^f together with the N-atom 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 Ci-C6-alkyl, as a ring member, or R^e, R^f and Rs 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. Further preferred tertiary amine bases are N-heteroaromatic compounds, where the N-atom is a ring- atom of the aromatic moiety. The N-heteroaromatic compounds are optionally substituted by 1 , 2, or 3 radicals selected from Ci-C4-alkyl, halogen, 1 -pyrrolidinyl, and di(Ci-C3-alkyl)amino. Suitable N-heteroaromatic compounds are pyridine, N-(Ci-C₄)- alkylimidazoles and quinolines, wherein the carbon atoms are unsubstituted or carry 1 , 2, or 3 radicals selected from Ci-C₄-alkyl, halogen, 1 -pyrrolidinyl, and di(Ci-C3-alkyl)- amino.

Examples of preferred tertiary amines include, but are not limited to tri-Ci-C6-alkyl amines (or (Ci-C6-alkyl)sN), such as trimethylamine, methyldiethylamine, methyldiisopropylamine and ethyldiisopropylamine, cyclohexyldimethylamine, cyclohexyldiethylamine, N-methylpiperidine, N-methylmorpholine,

Ν,Ν-dimethylpiperazine, 1 ,4-diazabicyclo[2.2.2]octane (DABCO),

1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1 ,8-diazabicyol[5.4.0]undec-7-ene (DBU), N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl, 4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine.

Particularly preferred bases for the reaction A are alcoholates and tertiary amines which are preferably selected from C1-C5-alkanolat.es, such as sodium methanolate, sodium ethanolate, sodium isopropanolate, potassium methanolate, potassium ethanolate or potassium isopropanolate, (Ci-C6-alkyl)₃N, DBU, DBN, DABCO,

N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl, 4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine. Especially preferred bases for the reaction A are selected from sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate, DBU, DABCO, N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 methyl groups,

4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine, in particular from DBU, DBN, DABCO, pyridine, sodium methanolate and sodium ethanolate, and specifically from DBU and sodium methanolate.

Cryptobases herein refer to reagents that have a hidden basicity, which evolves by attack of a nucleophile. Suitable cryptobases are, for example aliphatic and

cycloaliphatic epoxides, preferably having 2 to 6 carbon atoms, e.g. C2-C6- epoxyalkanes or Cs-Ce-epoxycycloalkanes. It is believed that in the presence of mild nucleophiles, such as the counteranions of Wittig-type phosphonium salts, epoxides can be converted via ring opening reaction to the respective alkoxylates.

Accordingly, in case the reaction A is carried out in the presence of a cryptobase, such as in particular an aliphatic or cycloaliphatic epoxide having 2 to 6 carbon atoms, it is preferred that in addition an anion, such as a halide anion, which may originate from the phosphonium salt of the formula (II), is also present. Thus, in a particular embodiment of the invention the reaction A is performed not only in the presence of a cryptobase but also in the presence of a halide anion which is preferably selected from chloride, bromide and iodide. In another particular embodiment of the invention the reaction A is performed in the presence of a cryptobase and the counteranion of the phosphonium salt of the formula (II) is a halide anion preferably selected from chloride, bromide and iodide. Preferably, the cryptobase for the reaction A of the inventive process is selected from C2-C6-epoxyalkanes, in particular from epoxypropane and 1 ,2-epoxybutane, and specifically is 1 ,2-epoxybutane. In a preferred embodiment of the invention the reaction A of the inventive process is carried out in the presence of a base selected from alcoholates and tertiary amines, such as in particular sodium methanolate, sodium ethanolate, DBU, DBN or DABCO, and especially sodium methanolate or DBU. In the reaction A the phosphonium salt of formula (II) and the 12'-apocarotenal of formula (III)) are reacted in a molar ratio within the range of typically 1 :1 to 3:1 , preferably 1 :1 to 2:1 , more preferably 1 .2:1 to 1 .8:1 and specifically 1 .3:1 to 1 .55:1.

If a base is employed in the reaction A, it is used in a total amount of typically 0.5 to 2.0 mol, preferably 0.5 to 1.6 mol, in particular 0.6 to 1 .4 mol, and specifically 0.7 to

1 .2 mol, based in each case on 1 mol of the phosphonium salt of formula (II). In case a tertiary amine, such as DBU, is employed as base, it is used in a total amount of typically 0.8 to 2.0 mol, preferably 1.0 to 1.5 mol and in particular 1 .0 to 1 .2 mol, while in case an alcoholate, such as sodium methanolate, is employed as base, it is used in a total amount of typically 0.5 to 1.5 mol, preferably 0.6 to 1 .2 mol and in particular 0.7 to 1 .0 mol, based in each case on 1 mol of the phosphonium salt of formula (II).

If a cryptobase is employed in the reaction A, it is used in a total amount of typically 1 .5 to 20 mol, preferably 2 to 10 mol, more preferably 3 to 8 mol, in particular 4 to 7 mol, and specifically 5 to 6 mol, based in each case on 1 mol of the phosphonium salt of formula (II).

The reaction of the inventive process is preferably carried out in an organic solvent. It has been found to be often advantageous to use an aprotic organic solvent, in particular a polar aprotic organic solvent, for the reaction A of the inventive process, especially if it is performed in the presence of a base. Useful aprotic organic solvents here include halogenated Ci-C4-alkanes, such as dichloromethane and

trichloromethane, Ci-C4-alkyl nitrile, such as acetonitrile, ethers, for example aliphatic C2-Cio-ethers having 1 , 2, 3, or 4 oxygen atoms, such as Ci-C4-alkoxy-Ci-C4-alkanes, e.g. diethyl ether, dipropyl ether, methyl isobutyl ether, methyl tert-butyl ether or ethyl tert-butyl ether, ethylene glycol dimethyl ether (glyme), diethylene glycol dimethyl ether (diglyme) and triethylene glycol dimethyl ether (triglyme), alicyclic C4-C6-ethers, such as tetrahydrofuran (THF), tetrahydropyran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran and 1 ,4-dioxane, aliphatic esters, such as Ci-C4-alkyl-Ci-C4- alkanoates, e.g. ethyl acetate or isopropyl acetate, aromatic hydrocarbons, such as benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, such as chlorobenzene, toluene, the xylenes and mesitylene, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or mixtures of these solvents with one another.

The solvent for the reaction A of the inventive process is preferably selected from halogenated Ci-C4-alkane, Ci-C4-alkyl nitrile, Ci-C4-alkoxy-Ci-C4-alkane, THF, 1 ,4-dioxane, Ci-C4-alkyl-Ci-C4-alkanoate, benzene optionally carrying 1 to 4

substituents selected from Ci-C4-alkyl and chlorine, DMF and NMP, and mixtures thereof, and in particular from dichloromethane, acetonitrile, methyl tert-butyl ether, THF, 1 ,4-dioxane, ethyl acetate, isopropyl acetate and toluene, and mixtures thereof.

Alternatively, in case the reaction A of the inventive process is performed in the presence of a cryptobase, the solvent may also be selected from protic organic solvents such as alcohols, e.g. Ci-C6-alkanols. A preferred protic organic solvent in this context is selected from ethanol, propanol, isopropanol, butanol, sec-butanol, isobutanol and tert-butanol, and in particular is ethanol or isopropanol. In one embodiment of the present invention the reaction A of the inventive process is carried out in the presence of a cryptobase and in a solvent that is selected from polar aprotic organic solvents, in particular those mentioned above as preferred, and protic organic solvents, such as in particular Ci-C6-alkanols that are preferably selected from Ci-C4-alkanols, more preferably from ethanol, propanol and isopropanol and specifically from ethanol and isopropanol.

The total amount of the solvent used in the reaction A of the inventive process is typically in the range from 500 to 10000 g, preferably in the range from 1000 to 7000 g and in particular in the range from 1500 to 6000 g, based on 1 mol of the phosphonium salt of formula (II).

Preference is given to using solvents which are essentially anhydrous, i.e. have a water content of less than 1000 ppm and especially not more than 200 ppm. The reactants can in principle be contacted with one another in any desired sequence. For example, the phosphonium salt of formula (II) and the 12'-apocarotenal of formula (III), if appropriate in dissolved or dispersed form, can be initially charged and mixed with each other. The obtained mixture can then be admixed with the base or the cryptobase. Conversely, phosphonium salt of formula (II), if appropriate in dissolved or dispersed form, can be initially charged and admixed with a mixture of the

12'-apocarotenal of formula (III) and the base or the cryptobase. Alternatively, all reactants can also be added simultaneously to the reaction vessel. As a further alternative the reactants can also be added separately to the reaction vessel, with the base or cryptobase being preferably added after the addition of the phosphonium salt of formula (II).

It has been found to be beneficial to initially charge the reaction vessel with the phosphonium salt of formula (II) or its mixture with the 12'-apocarotenal of formula (III), e.g. in dispersed form or preferably in dissolved form, and then to add the

12'-apocarotenal of formula (III), if applicable, followed by the addition of the base or cryptobase in a gradual manner or at once. The 12'-apocarotenal of formula (III) is employed as such or in dissolved form. In case a base is used it is preferably added gradually, while in case a cryptobase, such as in particular a (cyclo)aliphatic epoxide, is used, it may possibly be charged at once to the reaction vessel.

In general, the reaction A of the inventive process is performed under temperature control. The reaction is typically effected in a closed or preferably in an open reaction vessel with stirring apparatus. The reaction temperature of the inventive process depends on different factors, in particular on the base or cryptobase used, and can be determined by the person skilled in the art in the individual case, for example by simple preliminary tests. In general, the conversion of the inventive process is performed at a temperature in the range from -20 to 150°C, preferably in the range from -10 to 120°C, and in particular in the range from -5 to 100°C. In case a base is used in the reaction A, the temperature is preferably in the range from -20 to 50°C, more preferably from -10 to 25°C, in particular from -5 to 10°C and specifically in the range from -3 to 3°C, while in case a cryptobase is used in the reaction A, the temperature is preferably in the range from 0 to 150°C, more preferably from 5 to 120°C, in particular from 10 to 100°C and specifically in the range from 15 to 90°C.

According to one embodiment of the invention the reaction A of the inventive process is initiated at a lower temperature, for instance, if a cryptobase is used, at a temperature in the range of 5 to 40 and preferably 10 to 30°C, and the temperature is then increased to an upper temperature, for instance, if a cryptobase is used, to a temperature in the range of 50 to 150°C and preferably 60 to 100°C.

Depending on the solvent used, the reaction temperature and on whether the reaction vessel possesses a vent, a pressure of generally 1 to 5 bar and preferably of 1 to 3 bar is established during the reaction. The work-up of the reaction mixtures obtained in the reaction A of the inventive process and the isolation of the carotenoid mono-ester of formula (I) are effected in a customary manner, for example by a quenching step followed by an aqueous extractive work-up or removal of the solvent, for example under reduced pressure. Instead of removing the solvent it may alternatively be replaced in an isochoric distillation process with another solvent from which the product of formula (I) crystallizes. Alternatively, the organic phase obtained after the aqueous extractive work-up can be subjected to an isochoric distillation process to replace the solvent, followed by the crystallization of the product of formula (I). Frequently, the esters of formula (I) are obtained in sufficient purity by applying such measures or a combination thereof. Thus, additional purification steps, in particular elaborated ones such as chromatography are often not necessary. If desired, however, further purification can be effected by methods commonly used in the art. Preferably, as the initial step of the work-up, in case a base is used, the reaction A is quenched after completion of the conversion by preferably adding to the reaction mixture an acid or an aqueous solution thereof, such as acetic acid, usually followed by the addition of water. The aqueous phase is then removed, if applicable, and the organic phase is typically washed with water. In case a cryptobase is used such a quenching step may not be necessary. In particular if an aliphatic or cycloaliphatic epoxide is employed as cryptobase it is typically sufficient to remove the solvent after completion of the reaction and, if further work-up steps are intended, to re-dissolve or re-suspend the obtained residue in a suitable organic solvent. The organic phase containing the product of formula (I) that is obtained either with or without aqueous extractive work-up, as described above, may afterwards be introduced into a further reaction step, either directly or after partial or complete removal of the solvent, if applicable, and optional further purification steps, such as column

chromatography. Alternatively, the organic phase may be subjected to crystallisation conditions and after completion of the crystallisation the formed crystals are isolated, washed and dried. It is often advantageous to perform the crystallization in a solvent other than that used for the reaction. In that case the original solvent is replaced with one that is more appropriate for crystallization, for example by simply removing the original solvent, e.g. under reduced pressure, and re-dissolving the obtained residue in the new solvent, or, alternatively, by using an isochoric distillation process.

As mentioned before, a further aspect of the present invention relates to the process of the invention for preparing a carotenoid mono-ester of the formula (I) additionally comprising the preparation of the phosphonium salt of the formula (II), which comprises reacting a compound of the formula (IV) with a carboxylic acid or one of its derivatives of the formula (V), wherein the reaction is carried out in the presence of a tertiary amine and in case a compound of the formula (V) with Z = OH is used also in the presence of an activator. This reaction step, which is herein also called reaction B, is usually carried out prior to the reaction A, i.e. the conversion of the phosphonium salt of the formula (II) with 12'-apocarotenal of the formula (III) to afford the carotenoid mono- ester of the formula (I).

Suitable tertiary amines for the reaction B of the inventive process are those that are mention herein in the context of the reaction A. Preferred tertiary amines for the reaction B are (Ci-C6-alkyl)3N , DBU, DABCO, N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl,

4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine, in particular trimethylamine, N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 methyl groups,

4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine, and specifically

N-methylimidazole and pyridine.

Suitable activators for the reaction B of the inventive process are in principle all compounds capable of converting a carboxylic acid of the formula (V), i.e. the variable Z in formula (V) is -OH, into an corresponding activated ester or a mixed anhydride, which is able to convert an alcohol of formula (IV) in the presence of a tertiary amine into the desired phosphonium salt ester of formula (II). Preferred activators are

Ν,Ν'-dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Ν,Ν'-diisopropylcarbodiimide (DIC), 1 ,1 '-carbonyldiimidazole (CDI), pivaloyl chloride, Ci-C3-alkyl ester of chloroformic acid, phosgene, thionyl chloride and phosphoryl chloride, in particular DCC, EDC and DIC.

In the reaction B of the inventive process the phosphonium salt of formula (IV) and the carboxylic acid or one of its derivatives of formula (V) are reacted in a molar ratio within the range of typically 1 :1 to 1 :5, preferably 1 :1 to 1 :4, more preferably 1 :1 to 1 :3 and specifically 1 :1.1 to 1 :2. In particular, in case a carboxylic acid of formula (V) is used, i.e. Z in formula (V) is -OH, the molar ratio of the compounds (IV) and (V) is within the range of typically 1 :1 to 1 :2 and preferably 1 :1 to 1 :1.5, while in case a carboxylic acid derivative of formula (V) is used, i.e. Z in formula (V) is not -OH, the molar ratio of the compounds (IV) and (V) is within the range of typically 1 :1 .2 to 1 :5 and preferably 1 :1.5 to 1 :4.

In the reaction B of the inventive process the tertiary amine is used in an amount of typically 1 .0 to 3.0 mol, preferably 1 .0 to 2.0 mol, in particular 1 .0 to 1 .5 mol, and specifically 1.0 to 1 .3 mol, based in each case on 1 mol of the carboxylic acid or one of its derivatives of formula (V).

In the reaction B of the inventive process, if a carboxylic acid of formula (V) is used, i.e. Z in formula (V) is -OH, the activator is used in an amount of typically 1 .0 to 2.0 mol, in particular 1.0 to 1 .5 mol, and specifically 1 .1 to 1.3 mol, based in each case on 1 mol of the carboxylic acid of formula (V).

The reaction B of the inventive process is preferably carried out in an organic solvent.

It has generally been found to be advantageous to use an aprotic organic solvent, in particular a polar aprotic organic solvent, for the reaction B of the inventive process. Useful aprotic organic solvents here are those that have been mentioned herein in the context of the reaction A.

The solvent for the reaction B of the inventive process is preferably selected from halogenated Ci-C4-alkane, Ci-C4-alkyl nitrile, Ci-C4-alkoxy-Ci-C4-alkane, THF, 1 ,4-dioxane, Ci-C4-alkyl-Ci-C4-alkanoate, benzene optionally carrying 1 to 4

substituents selected from Ci-C4-alkyl and chlorine, DMF and NMP, and in particular from dichloromethane, acetonitrile, methyl tert-butyl ether, THF, 1 ,4-dioxane, ethyl acetate, isopropyl acetate and toluene.

The total amount of the solvent used in the reaction of the reaction B according to the invention is typically in the range from 1000 to 10000 g and preferably in the range from 2000 to 8500 g, based on 1 mol of the phosphonium salt of formula (IV).

Preference is given to using solvents which are essentially anhydrous, i.e. have a water content of less than 1000 ppm and especially not more than 200 ppm. The reactants of the reaction B of the inventive process can in principle be contacted with one another in any desired sequence. It has been found to be beneficial, however, to initially charge the reaction vessel with the phosphonium salt of formula (IV) or its mixture with the tertiary amine, e.g. in dispersed form or preferably in dissolved form, and then to add the tertiary amine, if applicable, followed by the addition of the carboxylic acid or its derivative of formula (V) in a gradual manner or at once. The carboxylic acid or its derivative of formula (V) is employed as such or in dissolved form. In case an activator is used it is preferably charged to the reaction vessel before, after or together with the phosphonium salt of formula (IV) and only thereafter the tertiary amine and the carboxylic acid of formula (V) with Z = -OH are successively added. In general, the reaction B of the inventive process is performed under temperature control. The reaction B is typically effected in a closed or preferably in an open reaction vessel with stirring apparatus. The reaction temperature of the inventive process depends on different factors, in particular on the reactivity of either the carboxylic acid derivative of formula (V) used or of the active ester formed from the carboxylic acid of formula (V), and can be determined by the person skilled in the art in the individual case, for example by simple preliminary tests. In general, the conversion of the inventive process is performed at a temperature in the range from -78 to 100°C, preferably in the range from -20 to 80°C, more preferably in the range from -10 to 60°C and specifically in the range from -5 to 50°C.

According to one embodiment of the invention the reaction B of the inventive process is initiated at a lower temperature, for instance at a temperature in the range of -10 to 40 and preferably -5 to 20°C, and the temperature is then increased stepwise or continuously to an upper temperature, for instance to an temperature in the range of 0 to 80°C and preferably 10 to 50°C.

The work-up of the reaction mixtures obtained in the reaction B of the inventive process and the isolation of the phosphonium salt ester of formula (II) are effected in a customary manner and is preferably carried out as follows:

As the initial step of the work-up process, the reaction B of the inventive process is quenched by adding to the reaction mixture, after completion of the conversion, a nucleophilic compound, such as an alcohol, e.g. methanol, water or a diluted acid such as an aqueous solution of acetic acid or hydrochloric acid. The aqueous phase is then removed, if applicable, and the organic phase is extracted with water or a diluted acid, such as an aqueous solution of acetic acid or of hydrochloric acid, usually followed by washing steps with water. The organic phase containing the phosphonium salt ester of formula (II) can afterwards be introduced into a further reaction step, either directly or after partial or complete removal of the solvent and optional further purification steps. Alternatively, the organic phase is subjected to crystallisation conditions and after completion of the crystallisation the formed crystals are isolated, washed and dried. It is often advantageous to perform the crystallization in a solvent other than that used for the reaction. In that case the original solvent is replaced with one that is more appropriate for crystallization, for example by simply removing the original solvent, e.g. under reduced pressure, and re-dissolving the obtained residue in the new solvent, or, alternatively, by using an isochoric distillation process. The phosphonium salts of the formula (IV) used as starting materials in the preparation of the phosphonium salts of the formula (II) can be prepared e.g. by analogy to the process disclosed in the prior art discussed at the outset. Compounds of the formula (IV), where X is Chb can e.g. be prepared by the process described by J. A. Haugan 1994, Acta Chem. Scand. 48, 657, via a Grignard reaction of 3-hydroxy-p-ionone or 3-oxo-4-hydroxy-p-ionone with vinylmagnesium bromide to obtain the corresponding tertiary Cis-alcohol, which is reacted with suitable phosphine reagent, such as triphenylphosphine hydrobromide, to afford the desired phosphonium salt of the formula (IV). Compounds of the formula (IV), where X is C=0 can e.g. be prepared by the process described by E. Becher et al. Helv. Chim. Acta 64 (1981 ), 2419.

The following examples are intended to serve as further illustration of the invention.

EXAMPLES

Hereinafter the following abbreviations are used:

aq. = aqueous

wt-% = % by weight

DCM = dichloromethane

MeOH = methanol

DBU = 1 ,8-diazabicyol[5.4.0]undec-7-ene

NaOMe = sodium methanolate

EtOAc = ethyl acetate Preparation Example 1 : (S)-3-Methyl-5-(4-palmitoyloxy-2,6,6-trimethyl-3-oxo-1 - cyclohexen-1 -yl)-2,4-pentadienyl-triphenylphosphonium bromide

(S)-3-Methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)-2,4-pentadienyl- triphenylphosphonium bromide (575.5 g, 1 mol) and DCM (2000 mL) were charged to a 4L reactor and cooled to a temperature of 0°C. Pyridine (1 19.6 g, 1512 mmol) was added and then palmitoyl chloride (358.7 g, 1375 mmol) metered in dropwise over a period of 1 hour. After stirring for further 18 hours at 0°C, water (1000 mL) was added and the mixture was heated to 20°C. The organic phase was separated from the aq. phase and washed with water (1000 mL). Afterwards the solvent of the organic phase was replaced with isopropyl acetate by means of an isochoric distillation under ambient pressure. After having added 2000 ml of isopropyl acetate seed crystals were added at a temperature of 20°C. After completion of the precipitation the formed solids were isolated, washed with isopropyl acetate (2 x 400 mL) and dried in a nitrogen stream over night at 20°C. The title compound was obtained in an amount of 707 g having a purity of 98.4 wt-%, which corresponds to 854.7 mmol and a yield of 85%.

Preparation Example 2: (S)-3-Methyl-5-(4-oleyloxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4-pentadienyl-triphenylphosphonium bromide

By analogy to preparation example 1 (S)-3-methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo- 1 -cyclohexen-1 -yl)-2,4-pentadienyl-triphenylphosphonium bromide was reacted with oleyl chloride to afford the title compound with a purity of > 90 wt-%.

Example 1 : (6S)-6-Palmitoyloxy-3-[(all-E)-18-[(4S)-4-hydroxy-2,6,6-trimethyl-3-oxo-1 - cyclohexenyl]-3,7,12, 16-tetramethyloctadeca-1 ,3,5,7,9,1 1 ,13,15,17-nonaenyl]-2,4,4- trimethyl-1 -cyclohex-2-enone ((3S,3'S)-Astaxanthin-mono-palmitate)

DCM (275 mL), (S)-3-Methyl-5-(4-palmitoyloxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 - yl)-2,4-pentadienyl-triphenylphosphonium bromide (61 g, 75 mmol) and (S)-2,7,1 1 - trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)-2,4, 6,8,10,12- tridecahexaen-1 -al (19 g, 50 mol) were successively charged to a glass reactor at a temperature of 0°C and then DBU (12.5 g, 82,5 mmol) was added dropwise. After continued stirring for 24 hours at 0°C acetic acid (1 ,5 g, 25 mmol) followed by water (150 mL) were added dropwise and the reaction mixture was warmed to a temperature of 20°C. The organic and aqueous phases were afterwards separated and the latter extracted with DCM (25 mL). The combined organic phases were washed with water (150 mL), the aqueous phase was extracted with DCM (25 mL), the combined organic phases were diluted with MeOH (500 mL) and the obtained mixture was subjected to an isochoric distillation in order to replace DCM with MeOH. After cooling to 20°C the crystallized solids were filtered off, the filter cake washed with MeOH (4 x 100 mL) and dried overnight under a stream of nitrogen. The title compound was obtained in an amount of 40.25 g.

Example 2: (6S)-6-Palmitoyloxy-3-[(all-E)-18-[(4S)-4-hydroxy-2,6,6-trimethyl-3-oxo-1 - cyclohexenyl]-3,7,12,16-tetramethyloctadeca-1 ,3,5,7,9,1 1 ,13,15,17-nonaenyl]-2,4,4- trimethyl-1 -cyclohex-2-enone ((3S,3'S)-Astaxanthin-mono-palmitate) DCM (275 mL), (S)-3-Methyl-5-(4-palmitoyloxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 - yl)-2,4-pentadienyl-triphenylphosphonium bromide (61 g, 75 mmol) and (S)-2,7,1 1 - trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)-2,4, 6,8,10,12- tridecahexaen-1 -al (19 g, 50 mol) were successively charged to a glass reactor at a temperature of 0°C and then a solution of NaOMe in MeOH (30 wt-%, 1 1.25 g, 62,5 mmol) was added dropwise. After continued stirring for 1 hour at 0°C acetic acid (1 ,5 g, 25 mmol) followed by water (150 mL) were added dropwise and the reaction mixture was warmed to a temperature of 20°C. The organic and aqueous phases were afterwards separated and the latter extracted with DCM (25 mL). The combined organic phases were washed with water (150 mL) and the aqueous phase was extracted with DCM (25 mL). The combined organic phases were then subjected to an isochoric distillation in order to replace DCM with MeOH. After cooling to 20°C the crystallized solids were filtered off, the filter cake washed with MeOH (4 x 100 mL) and dried overnight under a stream of nitrogen. The title compound was obtained in an amount of 37.1 g.

Example 3: (6S)-6-Palmitoyloxy-3-[(all-E)-18-[(4S)-4-hydroxy-2,6,6-trimethyl-3-oxo-1 - cyclohexenyl]-3,7,12, 16-tetramethyloctadeca-1 ,3,5,7,9,1 1 ,13,15,17-nonaenyl]-2,4,4- trimethyl-1 -cyclohex-2-enone ((3S,3'S)-Astaxanthin-mono-palmitate)

Isopropanol (156 mL), (S)-3-Methyl-5-(4-palmitoyloxy-2,6,6-trimethyl-3-oxo-1 - cyclohexen-1 -yl)-2,4-pentadienyl-triphenylphosphonium bromide (65.2 g, 77.6 mmol), (S)-2,7, 1 1 -trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4,6,8,10,12-tridecahexaen-1 -al (19.7 g, 51 .75 mol) and 1 ,2-epoxybutane (29.85 g, 414 mmol) were successively charged to a glass reactor at a temperature of 0°C and then heated under reflux for 16.5 hours. The solvent was then distilled off in a rotary evaporator and the obtained residue was subjected to column chromatography on silica gel using cyclohexane/EtOAc as eluent. Example 4: (6S)-6-Oleyloxy-3-[(all-E)-18-[(4S)-4-hydroxy-2,6,6-trimethyl-3-oxo-1 - cyclohexenylj-3,7,12, 16-tetramethyloctadeca-1 ,3,5,7,9,1 1 ,13,15,17-nonaenyl]-2,4,4- trimethyl-1 -cyclohex-2-enone ((3S,3'S)-Astaxanthin-mono-oleate)

Isopropanol (156 mL), (S)-3-Methyl-5-(4-oleyloxy-2, 6, 6-trimethyl-3-oxo-1 -cyclohexen-1 - yl)-2,4-pentadienyl-triphenylphosphonium bromide (65.2 g, 77.6 mmol),

(S)-2,7, 1 1 -trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4,6,8,10,12-tridecahexaen-1 -al (19.7 g, 51 .75 mol) and 1 ,2-epoxybutane (29.85 g, 414 mmol) were successively charged to a glass reactor at a temperature of 0°C and then heated under reflux for 16.5 hours. The solvent was then distilled off in a rotary evaporator and the obtained residue was subjected to column chromatography on silica gel using cyclohexane/EtOAc as eluent. The title compound was obtained in an amount of 21.9 g.

Claims

Claims

1 . A process for the preparation of a carotenoid mono-ester of the formula (I),

including the stereoisomers of formula (I), wherein, X¹, X² are identical or different and selected from the group consisting of Chb and

C=0;

R¹ is selected the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, C10-C20- alkpentaenyl, Ci-C4-alkoxy, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the seven aforementioned residues are unsubstituted or carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH and Ci-C4-alkoxy,

C6-Cio-aryl, benzyl, phenoxy, benzoxy, where the aryl moieties of the four aforementioned residues are unsubstituted or carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH, Ci-C4-alkyl and C1-C4- alkoxy,

A-COOH, A-CONH2, A-COO-(Ci-C₄-alkyl), and

A-NR^aR^b,

R² and R³ are each independently from one another selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl,

C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, Ci-C4-alkoxy, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the seven aforementioned residues are unsubstituted or carry 1 , 2 or 3 substituents selected from the group consisting of halogen and Ci-C₄-alkoxy,

R² may also be selected from the group consisting of

-COOH, -COO-(Ci-C₄-alkyl), and

-NR^aR^b, or R¹ and R² together form a grou of the formula (1-1 ),

or

R¹, R² and R³ together form a group of the formula (I-2),

* — R

(I-2)

or if R² is -NR^aR^b, R¹ together with R^a may form a C3-C4-alkandiyl group, and where, irrespectively of their occurrence,

^* in formulae (1-1 ) and (I-2) indicate the point of attachment to the remainder of the molecule;

R^a is selected from the group consisting of hydrogen, Ci-C4-alkyl,

-C(0)H, -C(0)-Ci-C3-alkyl, C4-C7-cycloalkyl, and N-protecting groups such as tert-butyloxycarbonyl (-Boc) and carboxybenzyl (-Cbz),

R^b is selected from the group consisting of hydrogen, Ci-C4-alkyl,

-C(0)-Ci-C3-alkyl, and N-protecting groups such as -Boc and -Cbz, and

R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl,

C2-Ci9-alkenyl, C4-Cig-alkdienyl, C6-Ci9-alktrienyl, Cs-dg-alktetraenyl, Ci-C₄-alkandiyl-COOH, C2-C₄-alkendiyl-COOH and C2-C₄-alkyndiyl-COOH,

R^d is hydrogen or Ci-C4-alkyl, and

A is selected from the group consisting of d-Cs-alkandiyl, C2-Cs-alkendiyl and C2-C5-alkyndiyl; which comprises reacting a phosphonium salt of the formula (II) or a

stereoisomer thereof:

wherein X¹, R¹, R², and R³ are as defined for formula (I), R⁴ is selected from the group consisting of phenyl, tert-butyl and tolyl, and

Y^" is selected from the group consisting of halide, sulfate, hydrogensulfate, mesylate, tosylate, benzenesulfonate, nitrate and Ci-C3-alkyl-carboxylate, with a 12'-apocarotenal of the formula (III) or a stereoisomer thereof:

wherein X² is as defined for formula (I), in the presence of a base or a cryptobase.

The process according to claim 1 , where the reaction is performed in the presence of a base, which is selected from the group consisting of tertiary amines and alcoholates.

The process according to claim 2, where the tertiary amine is selected from the group consisting of (Ci-C6-alkyl)sN, 1 ,8-diazabicycloundec-7-ene (DBU), 1 ,4-diazabicyclo[2.2.2]octane (DABCO), N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl,

4-(dimethylamino)pyridine, 4-(1 -pyrrolidinyl)pyridine and where the alcoholate is selected from the group consisting of alkalimetal C1-C5-alkanolat.es.

The process of any one of claims 2 or 3, where the total amount of base is in the range from 0.5 to 2 mol, in particular from 0.8 to 1.5 per mol of the phosphonium compound of the formula (II).

The process of claim 1 , where the reaction is performed in the presence of a cryptobase, which is selected from the group of an aliphatic or cycloaliphatic epoxide having 2 to 6 carbon atoms.

The process of claims 5, where the cryptobase reaction is performed in the presence of halide anions, selected from chloride, bromide or iodide.

7. The process of any one of claims 5 or 6, where the total amount of crypotbase is in the range from 1.5 to 20 mol, in particular from 2 to 10 mol per mol of the phosphonium compound of the formula (II).

The process according to any one of the preceding claims, where the molar ratio of the compound of formula (II) to the compound of formula (III) is in the range from 1 :1 to 2:1 .

The process according to any one of the preceding claims, where the reaction is performed in an aprotic solvent, which is preferably selected from the group consisting of benzene optionally carrying 1 to 4 substituents selected from C1-C4- alkyl and chlorine, Ci-C4-alkoxy-Ci-C4-alkane, halogenated Ci-C4-alkane, C1-C4- alkyl nitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), tetrahydrofurane (THF), 1 ,4-dioxane and C1-C4-alkyl-C1-C4-alkanoat.es and mixtures thereof.

The process according to any one of the preceding claims, wherein in formulae (I) and (II):

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, A-COOH, A-CONH2 and A-COO-(Ci-C₄-alkyl), where A has the meaning defined in claim 1 ,

R² is hydrogen or -NR^aR^b, wherein R^a and R^b have the meanings defined in claim 1 , or

R¹ and R² together form a group of the formula (1-1 ), wherein

R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl,

C2-Ci9-alkenyl, C4-Cig-alkdienyl, C6-Ci9-alktrienyl and Cs-Cig- alktetraenyl, and

R^d is hydrogen, and

R³ is hydrogen.

The process according to any one of the preceding claims, wherein in formulae (I) and (II):

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C₄-C₂o-alkdienyl, C₆-C₂o-alktrienyl, C₈-C₂₀- alktetraenyl, A-COOH, A-CONH2 and A-COO-(Ci-C₄-alkyl), where A is CH₂ or CH₂CH₂;

R² is hydrogen or -NR^aR^b, wherein

R^a is selected from the group consisting of hydrogen, Ci-C4-alkyl,

-C(0)-Ci-C₃-alkyl, -Boc and -Cbz, R^b is selected from the group consisting of hydrogen and Ci-C4-alkyl, and

R³ is hydrogen. 12. The process according to any one of the preceding claims wherein the moiety -C(0)CR¹R²R³ in formulae (I) or (II) is selected from the group consisting of lauroyi, myristoyl, linoleoyi, a-linolenoyl, γ-linolenoyl, succinoyi and arachidonoyi, in particular lauroyi and γ-linolenoyl. 13. The process according to any one of claims 1 to 1 1 wherein the moiety

-C(0)CR¹R²R³ in formulae (I) or (II) is selected from the group consisting of N-Boc-glycyl, N-Cbz-glycyl, N-Boc-sarcosinyl and N-Cbz-sarcosinyl, in particular is N-Boc-sarcosinyl.

14. The process according to any one of the preceding claims, which further

comprises the preparation of the phosphonium salt of the formula (II), which comprises reacting a compound of the formula (IV)

wherein the variables X¹, R⁴ and Y- have the meanings defined in claim 1 , with a carboxylic acid or one of its derivatives of the formula (V),

wherein

the variables R¹, R² and R³ have the meanings defined in claim 1 , and for n = 1 the variable Z is selected from the group consisting of halogen, -OH, -0-C(0)-Ci-C₄-alkyl, and

for n = 2 the variable Z is O or S, wherein the reaction is carried out in the presence of a tertiary amine and in case a compound of the formula (V) with Z = OH is used also in the presence of an activator. The process according to claim 14, wherein the tertiary amine is selected from the group consisting of (Ci-C6-alkyl)3N , 1 ,8-diazabicycloundec-7-ene (DBU), 1 ,4-diazabicyclo[2.2.2]octane (DABCO), N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl,

4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine.

The process according to any one of claims 14 or 15, wherein the activator is selected from the group consisting of Ν,Ν'-dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),

Ν,Ν'-diisopropylcarbodiimide (DIC), 1 ,1 '-carbonyldiimidazole (CDI), pivaloyl chloride, Ci-C3-alkyl ester of chloroformic acid, phosgene, thionyl chloride and phosphoryl chloride. 17. The process according to any one of claims 14 to 16, wherein the reaction

between the compounds of formulae (IV) and (V) is carried out in a polar, aprotic organic solvent, which is preferably selected from the group consisting of benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, Ci-C4-alkoxy-Ci-C4-alkane, halogenated Ci-C4-alkane, Ci-C4-alkyl nitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),

tetrahydrofurane (THF), 1 ,4-dioxane and Ci-C4-alkyl-Ci-C4-alkanoate.

18. The process according to any one of the claims 14 to 17, wherein the compounds of formulae (IV) and (V) are reacted in a molar ratio within the range of 1 : 1 to 1 :3 and preferably 1 :1.1 to 1 :2.