WO2018050793A1

WO2018050793A1 - Process for preparing phosphonium salt esters as building blocks for carotenoides

Info

Publication number: WO2018050793A1
Application number: PCT/EP2017/073219
Authority: WO
Inventors: Bernd Schaefer; Wolfgang Siegel
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2016-09-16
Filing date: 2017-09-15
Publication date: 2018-03-22
Anticipated expiration: 2019-03-16
Also published as: CN109715638A

Abstract

The present invention relates to a process for preparing a phosphonium salt ester of the 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, X is CH₂ or C=O, R⁴ is phenyl, tert-butyl or tolyl, Y^- is a suitable counteranion, the process being characterized in that an alcohol of the formula (IV), is reacted with a carboxylic acid or one of its derivatives of the formula (V), wherein the variables R¹, R² and R³ are as defined above, and for n = 1 the variable Z is halogen, -OH or -O-C(O)-C₁-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 (IV) with Z = -OH is used also in the presence of an activator. The invention further relates to certain phosphonium salt esters of the formula (I).

Description

Process for preparing phosphonium salt esters as building blocks for carotenoides

The present invention relates to a new process for preparing a phosphonium salt ester of the formula (I),

wherein R¹, R², R³, R⁴, X, and Y^" are as defined herein. BACKGROUND OF THE INVENTION

Phosphonium salt esters of formula A,

wherein the variable R is acetyl, chloroacetyl, dichloroacetyl, ethoxyacetyl,

phenoxyacetyl, propionyl, butyryl, pentanoyi, hexanoyi, palmitoyi, stearoyi or oleoyi, the variable V is an aryl group such as phenyl and the variable T- is a suitable anion such as bromide, have been disclosed in DE 26 53 838, DE 44 30 289, F. Kienzle et al. 1978, Helv. Chim. Acta 61 , 2609 and J. Liu et al. 1997, Tetrahedron Lett. 38, 8495 as intermediates for the synthesis of astaxanthins and their symmetric diesters. Likewise, phosphonium salt esters that slightly differ from those of formula (A) in that they have a modified exocyclic side chain were used as precursors for the syntheses of carotenoids and related polyenes, as documented e.g. in Y. Yamano et al. 1995, J. Chem. Soc. Perkin Trans. 1 , 1895; Y. Yamano et al. 1994, Chem. Pharm. Bull. 42, 410 and K. Bernhard et al. 1980, Helv. Chim. Acta 63,1473. In these syntheses the acyl group R functioned merely as an intermediate protection group.

So far phosphonium salt esters of formula A and close variants thereof have been prepared by initially introducing the ester group and only afterwards forming the phosphonium salt moiety in subsequent reaction steps. However, this approach turns out to be tedious and expensive. SUMMARY OF THE INVENTION

It is an object of the present invention to provide a process for preparing phosphonium salt esters of formula A and variants thereof which process does not involve the problems of the prior art. The process should in particular be simple to perform and should enable good yields of the desired phosphonium salt esters.

It has been found that this object can indeed be achieved by acylating the unesterified phosphonium salts of the formula (IV),

wherein R⁴, X, and Y^" are as defined herein, with a carboxylic acid or an activated carboxylic acid in the presence of a tertiary amine. This finding is surprising because phosphonium salts are generally known to be labile and to decompose under conditions typically used for acylations, such as in particular the use of bases, of strong acids or of milder acids in combination with higher temperatures. Therefore a person skilled in the art would not have expected that an efficient esterification of phosphonium salts of the formula (IV) would be possible. This is especially true since the

phosphonium salts of the formula (IV) are even labile towards mild bases, due to their polyene structure substituted with an electron acceptor.

Accordingly, the invention firstly relates to a process for the preparation of a

phosphonium salt ester of the formula (I), which comprises reacting a phosphonium salt 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.

In formula (I) the variables R¹, R², R³, R⁴, X, and Y^" 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, 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, C_o-C20-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 (II),

wherein

_* is the attachment point to the remainder of the molecule,

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

C2-Ci9-alkenyl, C4-Cig-alkdienyl, C6-Ci9-alktrienyl, C₀-Ci9-alktetraenyl, Ci-C₄-alkandiyl-COOH, C₂-C₄-alkendiyl-COOH, C₂-C₄-alkyndiyl-COOH, and R^d is hydrogen or Ci-C4-alkyl, or

R² and R³ together form a group of the formula (III),

wherein * and R^c have the meanings defined above, or

if R² is -NR^aR^b, R¹ together with R^a may form a C3-C4-alkandiyl group,

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

X is CH₂ or C=0, Y^" is selected from the group consisting of halide, sulfate, hydrogensulfate, mesylate, tosylate, benzenesulfonate, nitrate and Ci-C3-alkyl-carboxylate, 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

A is selected from the group consisting of d-Cs-alkandiyl, C2-Cs-alkendiyl and C2-

C5-alkyndiyl.

In formulae (IV) the variables X, Y^" and R⁴ have the meanings defined for formula (I).

In formula (V) the variables R¹, R² and R³ have the meanings defined for formula (I), 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.

The invention further relates to phosphonium salt esters of the formula (I) 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 process has several advantages. First of all it affords an easy access to the phosphonium salt esters of the formula (I) in good yields and good specificity by starting from the corresponding unesterified phosphonium salt of the formula (IV).

Accordingly, the inventive process allows for the straightforward preparation of a series of phosphonium salt esters of the formula (I) with different acyl groups starting from a single phosphonium salt of the formula (IV), which itself is generally readily accessible in sufficient quantities and also storable.

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 tetradecenyl which may differ in the position and configuration of the double bond and the type of the possible branching, such as (7Z)-tetradecenyl and (4Z)-tetradecenyl, 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,

1 ,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, 1 1 ,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 ,4,7,10,12-tridecapentaenyl, 2,4,6,8, 10-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, 2,5,8,1 1 ,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 process of the invention, the reaction conditions and also of compounds of formulae (I), (la), (II), (III), (IV), (IVa) and (V) involved in the process, especially with respect to their substituents R¹, R², R³, R⁴, X, Z, A, R^a, R^b, R^c, R^d and Y-, are valid both on their own and, in particular, in every possible combination with each other.

The variable Y- in formulae (I) and (IV) is an anion equivalent serving as counterion to balance the positively charged phosphonium group and can in principle be selected freely from among monovalent anions and the proportions of polyvalent anions corresponding to a single negative charge. Examples of suitable anions are in particular those indicated above.

The two double bonds in the exocyclic chain of the compounds of formulae (I) and (IV) may independently from each other have E or Z configuration. According to preferred groups of embodiments of the present invention the compounds of formulae (I) and (IV) predominately have E configuration, i.e. the compounds of formulae (I) and (IV) contain a high proportion of formulae (la) and (IVa), respectively:

In the process of the invention, the compound of formula (IV) used for the reaction with the compound of formula (V) contains a high proportion of the E,E isomer (IVa), i.e. the amount of the E,E isomer IVa is frequently at least 80 mol-%, in particular at least 90 mol-% more particularly at least 95 mol-% and specifically at least 98 mol-% of the total amount of the compound of formula (IV). In the process of the invention, the configurations of the two exocyclic C-C double bonds usually remain essentially unchanged during the process of the invention, i.e. their configurations in the product of the formula (I) is essentially the same as in the educt of the formula (IV). Thus, the configurations of the exocyclic C-C double bonds of the educt of formula (IV) correspond to the configurations of the exocyclic C-C double bonds of the product of formula (I) to a degree of at least 80%, in particular to a degree of at least 90%. In particular an educt of formula (IV) with essentially all two exocyclic C-C double bonds being E configurated, i.e. at least 90 mol-%, preferably at least 95 mol-% and in particular at least 98 mol-% of the educt have an E,E configuration as depicted in formula (IVa), is converted to a product of formula (I) with essentially all two exocyclic C-C double bonds being E configurated, i.e. at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-% of the product of formula (I) have an E,E configuration as depicted in formula (la).

The compounds of the formulae (I), (la), (IV), (IVa) 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 (1-1 ), (IV-1 ), (I-2) and (IV-2), respectively:

According to a preferred embodiment the compounds of formulae (I) and (IV) with X being C=0 are predominately, 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 (1-1 ) or (IV-1 ). Likewise, according to a further preferred embodiment the compounds of formulae (I) and (IV) with X being Chb are predominately, 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 (1-1 ) or (IV-1 ). Preferably, the variables R¹, R², R³ in the compounds of formulae (I), (la) 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-CONH2, A-COO-(Ci-C₄-alkyl), Ci-C₄-alkoxy and phenoxy, in particular hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C₄-C2o-alkdienyl, C6-C20- alktrienyl, C₈-C₂o-alktetraenyl, Cio-C₂o-alkpentaenyl, A-COOH, A-CONH2 and A-COO-(Ci-C₄-alkyl) and specifically Ci-C₂o-alkyl, C₂-C₂o-alkenyl, C4-C20- alkdienyl, C₆-C₂o-alktrienyl, C₈-C₂o-alktetraenyl, 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 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 (II) or (III), in particular may form a group of formula (II) only, and specifically do not form a group of formulae (II) or (III). 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), (la) 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 R⁴ and Y- in the compounds of formulae (I), (la), (IV) and (IVa) have the following meanings:

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

particular is phenyl,

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 X in the compounds of formulae (I), (la), (IV) and (IVa) has the following meaning:

X is CH2 or C=0 and in particular C=0. According to one embodiment of the invention the variable X in formulae (I), (la), (IV) and (IVa) is CH₂.

According to a preferred embodiment of the invention the variable X in formulae (I), (la), (IV) and (IVa) is C=0.

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 compound of formula (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 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), (la) 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 variable X in in formulae (I), and (la) is especially C=0. According to a second group of embodiments of the invention the group -C(0)CR¹R²R³ in formulae (I), (la) 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 variable X in in formulae (I), and (la) is especially C=0. According to a third preferred group of embodiments of the invention the group

-C(0)CR¹R²R³ in formulae (I), (la) 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 X in in formulae (I), and (la) is 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 3 to 20 C-atoms, in particular having 8 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-protected a-amino acids, in particular 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 of the process according to the invention for preparing a phosphonium salt ester of the formula (I) may be regarded as an esterification or an acylation reaction. The conversion is effected by reacting a phosphonium salt of the formula (IV) with a carboxylic acid or one of its derivatives of the formula (V) in the presence of a tertiary amine and, in case a free carboxylic acid is used as the compound of formula (V), also in the presence of an activator.

Suitable tertiary amines are amines of the formula (A)

NR^eR^fR9 (A) where R^e, R^f and Rs, 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^e and R^f together with the nitrogen 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 suitable tertiary amines 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 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, N,N-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.

Preferred tertiary amines for the transformation of the inventive process are C1-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 transformation 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 (I). 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 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 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 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 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 of the inventive process. 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 C1-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 C1-C4-alkyl-C1-C4-alkanoat.es, 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 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 process 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 can in principle be contacted with one another in any desired sequence. For example, the phosphonium salt of formula (IV) and the tertiary amine, 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 carboxylic acid or its derivative of the formula (V). Conversely, the carboxylic acid or its derivative of formula (V), if appropriate in dissolved or dispersed form, can be initially charged and admixed with a mixture of the phosphonium salt of formula (IV) and the tertiary amine. Alternatively, all reactants can also be added simultaneously to the reaction vessel. As an alternative to the joint addition of the phosphonium salt of formula (IV) and the tertiary amine they can also be added separately to the reaction vessel. Both of them can independently of one another be added, either in a solvent or in bulk, before or after the addition of the carboxylic acid or its derivative of formula (V). In case a carboxylic of formula (V) is used (Z = -OH) the activator may be added before or after the addition of the carboxylic acid. It has been found to be beneficial 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 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 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 of the inventive process is initiated at a lower temperature, for instance at a temperature in the range of -10 to 40°C 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.

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 of the inventive process and the isolation of the phosphonium salt 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 phosphonium salt ester of formula (I) crystallizes. Frequently, the phosphonium salt 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 or distillation 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, the reaction of the inventive process is quenched by adding to the reaction mixture obtained in the reaction 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 (I) 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 inventive process 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 a 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.

As mentioned before, the present invention also relates to the phosphonium salt esters of formula (I) as such, wherein the aforementioned statements regarding their preferred characteristics, such as the enantiomeric configuration in position 3 of the 6-membered cycle , the configuration of the exocyclic chain and the meanings of the variables R¹, R², R³, R⁴, X and Y-, fully apply here, too, with the only exception that the group -C(0)R¹R²R³ in formula (I) is not acetyl, ethoxyacetyl, phenoxyacetyl, propionyl, butyryl, pentanoyl, hexanoyl, palmitoyl, stearoyl or oleoyl.

Preferred phosphonium salt esters of the formula (I) are those which include the group -C(0)CR¹R²R³ selected from the group consisting of lauroyl, myristoyl, linoleoyl, a-linolenoyl, γ-linolenoyl, arachidonoyl, N-Boc-glycyl, N-Cbz-glycyl, glycyl, succinoyl, N-Boc-sarcosinyl, sarcosinyl and N-Cbz-sarcosinyl, and in particular lauroyl, γ-linolenoyl and N-Boc-sarcosinyl.

The phosphonium salt esters of the formula (I) may serve as a starting material for the preparation of asymmetric diesters of carotenoid-type tetraterpenes but also of monoesters of symmetric carotenoid-type tetraterpenes, such as monoesters of astaxanthin or zeaxanthin. The monoesters as well as the asymmetric diesters can be prepared from the phosphonium salt esters of the formula (I) via Wittig reaction or a Julia olefination with the corresponding 12'-apocarotenals such as, 12'- apozeaxanthinal and 12'-apoastaxanthinal, respectively. 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

EDC = 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

NMI = 1 -methylimidazole

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%. Example 2: (R)-3-Methyl-5-(4-palmitoyloxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4-pentadienyl-triphenylphosphonium bromide

By analogy to example 1 (R)-3-Methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 - cyclohexen-1 -yl)-2,4-pentadienyl-triphenylphosphonium bromide (1 15.1 g, 200 mmol) was reacted with palmitoyl chloride (71 .7 g, 275 mmol) to afford 137.7 g of the title compound with a purity of 92.8 wt-%, corresponding to 153.6 mmol and a yield of 77%.

Example 3: (S)-3-Methyl-5-(4-lauroyloxy-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 (20 g, 34.75 mmol), DCM (276.7 g) and pyridine (4.81 g, 60.8 mmol) were charged to a 750 mL reactor followed by the dropwise addition of lauroyl chloride (1 1.4 g, 52.1 mmol) to the mixture at a temperature of 20°C. The reaction mixture was then heated under reflux for 23.5 hours. After the addition of MeOH (0.5 mL) the reaction mixture was extracted initially with an aq. solution of acetic acid (10 wt-%, 1 10 mL) and then with water (2 x 1 10 mL). The organic phase was concentrated by evaporation and the obtained residue was subjected to column chromatography on silica gel using DCM/MeOH 10:1 (v/v) as eluent. The main fraction contained 4.54 g of the title compound.

Example 4: (S)-3-Methyl-5-(4-(N-Boc-sarcosinyloxy)-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 (57.6 g, 100 mmol), DCM (400 mL) and EDC (28.75 g, 150 mmol) were charged at a temperature of 20°C to a 1 L three-necked flask. After cooling the mixture to a temperature of 0°C NMI (12.3 g, 150 mmol) and N-Boc- sarcosine (22.7 g, 120 mmol) were successively added and stirring was continued for 24 hours at 0°C. An aq. solution of hydrochloric acid (10 wt-%, 100 mL) was subsequently added, the organic phase separated from the aq. phase and washed initially with the aq. solution of hydrochloric acid (10 wt-%, 100 mL) and then with water (2 x 100 mL). Finally the organic phase was dried over sodium sulfate and reduced to dryness affording 73.6 g of the title compound.

Example 5: (S)-3-Methyl-5-(4-(y-linolenoyloxy)-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 (51.5 g, 84.4 mmol), DCM (666.5 g) and pyridine (20 g, 253.2 mmol) were charged to a 2.5 L reactor followed by the dropwise addition of γ-linolenoyl chloride (62.6 g, 21 1 mmol) to the mixture at a temperature of 20°C. The reaction mixture was then heated under reflux for 15 hours. After cooling down to 20°C MeOH (15.6 mL) was added dropwise and the mixture was then kept at a temperature of 30°C for 1.5 hours. The reaction mixture was afterwards extracted initially with an aq. solution of acetic acid (10 wt-%, 200 mL) and then with water (2 x 200 mL). The organic phase was dried over sodium sulfate and concentrated to dryness in a rotary evaporator at a temperature of 40°C and a pressure of 50 mbar affording 1 10.6 g of a viscous, brown oil which was dissolved in a mixture of cyclohexane/ ethyl acetate 2:1 (v/v) and subjected to column chromatography on silica gel using DCM/MeOH 20:1 (v/v) as eluent. 50.7 g of the title compound were obtained.

Claims

1 . A process for the preparation of a phosphonium salt ester of the formula (I),

wherein,

R¹ is selected the group consisting of hydrogen, Ci-C2o-alkyl, C2-C20- 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, -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 Ci-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-C20- 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 group of the formula (II),

wherein * is the attachment point to the remainder of the molecule, 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, C₂-C₄-alkyndiyl-COOH, and

R^d is hydrogen or Ci-C₄-alkyl, or

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

*: (ill) wherein * and R^c have the meanings defined above, or

if R² is -NR^aR^b, R¹ together with R^a may form a C3-C₄-alkandiyl group, R⁴ is selected from the group consisting of phenyl, tert-butyl and tolyl, X is CH₂ or C=0,

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

hydrogensulfate, mesylate, tosylate, benzenesulfonate, nitrate and C 1 -C3-a I ky l-ca rboxy I ate ,

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

A is selected from the group consisting of d-Cs-alkandiyl, C2-C5- alkendiyl and C2-Cs-alkyndiyl; the process being characterized in that a phosphonium salt of the formula

(IV),

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

wherein

the variables R¹ , R² and R³ have the meanings defined above, 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.

2. The process according to claim 1 , wherein the phosphonium salt of the formula (IV) comprises at least 80 mol-%, in particular at least 90 mol-% of the all-E isomer of the formula (IVa),

3. The process according to claim 1 or 2, wherein in formulae (I) and (V):

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C20- alkenyl, C₄-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, C10-C20- alkpentaenyl, A-COOH, A-CONH2 and A-COO-(Ci-C₄-alkyl), wherein 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 (II), wherein

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

R^d is hydrogen, and

R³ is hydrogen.

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

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C20- alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, A-COOH, A-CON H2 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 C1-C4- alkyl, and

R³ is hydrogen.

The process according to any one of the preceding claims, wherein in formulae (I) and (IV) the variable X is C=0.

The process according to any one of the preceding claims, wherein the carboxylic acid or one of its derivatives of the formula (V) are selected from the group consisting of acetic anhydride, succinic anhydride, saturated and unsaturated fatty acids having 8 to 20 C-atoms, the chlorides of saturated and unsaturated fatty acids having 8 to 20 C-atoms, and N-Boc or N-Cbz protected a-amino acids selected from glycine, sarcosine, proline, alanine, valine, leucine and isoleucine.

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

9. The process according to any one of the preceding claims, 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 C1-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.

10. The process according to any one of the preceding claims, wherein the reaction between the compounds of formulae (IV) and (V) is carried out at a temperature in the range of -78°C to 100°C, and preferably in the range of -20°C to 80°C.

1 1 . The process according to any one of the preceding claims, 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.

12. A phosphonium salt ester of the formula (I),

wherein X, R¹, R², R³ and R⁴ are as defined in one of claims 1 , 3, 4 or 5, except for the compound of the formula (I), wherein -C(0)CR¹R²R³ is acetyl, ethoxyacetyl, phenoxyacetyl, propionyl, butyryl, pentanoyl, hexanoyl, palmitoyl, stearoyl or oleoyl.

The phosphonium salt ester according to claim 12, which is or comprises at least 80 mol-%, in particular at least 90 mol-% of the all-E isomer of the formula (l

(la)

14. The phosphonium salt ester to any one of claims 12 or 13 wherein the group -C(0)CR¹R²R³ in formulae (I) or (la) is selected from the group consisting of lauroyl, myristoyl, linoleoyl, a-linolenoyl, γ-linolenoyl, arachidonoyl and succinoyl.

15. The phosphonium salt ester to any one of claims 12 or 13 wherein the group -C(0)CR¹R²R³ in formulae (I) or (la) is selected from the group consisting of N-Boc-glycyl, N-Cbz-glycyl, N-Boc-sarcosinyl, N-Cbz- sarcosinyl, glycyl and sarcosinyl.