WO2008003737A1

WO2008003737A1 - Method for producing 3,3'-dihydroxyisorenieratine and novel intermediate products therefor

Info

Publication number: WO2008003737A1
Application number: PCT/EP2007/056794
Authority: WO
Inventors: Hansgeorg Ernst; Hagen Jaedicke; Klaus Henrich
Original assignee: Basf Se
Priority date: 2006-07-07
Filing date: 2007-07-05
Publication date: 2008-01-10
Also published as: TW200811095A

Abstract

The invention relates to a novel method for producing 3,3'-dihydroxyisorenieratine of formula (I), and to novel intermediate products obtained according to said method.

Description

Process for the preparation of 3,3'-dihydroxyisorenieratin and novel intermediates therefor

description

The present invention relates to a novel process for the preparation of 3,3'-Dihydroxyisorenieratin in the formula I, hereinafter referred to Φ, Φ-carotene-3,3'-diol, as well as novel intermediates of this method.

3,3'-Dihydroxyisorenieratin (Φ, Φ-carotene-3,3'-diol) of the formula I is used as a feed additive (broiler skin pigmentation: Riv Zootec Vet 1974, 1, 31-44, egg yolk pigmentation: Z Allg. Microbiol. (1970), 10 (4), 237-244) are of great interest.

In the literature, various approaches to the fermentative production of

Φ, Φ-carotene-3,3'-diol described. These methods generally have a very low space / time yield. In addition, the purification of the pure pigment of the formula I requires very complicated purification operations which make a technically economical realization difficult (J. Ind. Microbiol Biotechnol., 24, 1, 64-70 (2000); Riv. Zootec., Vet. 1974, 1, 31-44; Phytochemistry 22, 11, 207-210, 1983). For the preparation of pure Φ, Φ-carotene-3,3'-diol of formula I, therefore, the total chemical synthesis is the path of choice.

DE 1593440 describes the synthesis of Φ, Φ-carotene-3,3'-diol of the formula I. In the final stage of this synthesis, according to the following reaction scheme, crocetine dialdehyde 1 is reacted with two equivalents of the phosphonium salt 2 in a double Wittig olefination according to the synthesis strategy C10 + C20 + C10 to form Φ, Φ-carotene-3,3'-diol of the formula I.

Φ, Φ-carotene-3,3'-diol According to DE 1593440, Example 2, from 2.58 g (8.72 mmol) of dialdehyde of the formula 1 after deprotection only 1, 5 g of Φ, Φ-carotene-3,3'-diol of the formula I (2.68 mmol = 30.7% of theory). This yield is too low for a technical process.

The phosphonium salt of the formula 2 required for this synthesis is prepared in a four-step sequence from 2,3,6-trimethyl-4-hydroxybenzaldehyde of the formula II. According to DE-1593440, Example 1, obtained from 14.6 g (89.02 mmol) of aldehyde of the formula II, only 6.4 g (11, 13 mmol) of the phosphonium salt of formula 2. This yield is not satisfactory.

4 steps

12.5% d. theory

R = tetrahydropyranyl protecting group

It was an object of the present invention, starting from technically available precursors to develop a new, technically and economically useful method for the preparation of Φ, Φ-carotene-3,3'-diol of the formula I. A further object was to make available novel intermediates for the novel process for preparing Φ, Φ-carotene-3,3'-diol of the formula I.

This object is achieved by a process for the preparation of 3,3'-Dihydroxyiso- renieratin in the formula I,

comprising at least one of the steps: a) Reaction of a monoketal of the formula II

wherein the radicals R ^{1 are} identical or different, preferably identical and are a Ci-Cs-alkyl group, or the two radicals R ¹ together represent a bivalent C2-Ci2-alkylene radical, that is, together with the atoms connecting them form a cyclic ketal, in particular a 5- or 6-ring ketal,

with a metalated alkyne of the formula IMa or IMb

in which R ^{2 is} an ether, silyl ether or acetal protecting group which can be converted by hydrolysis into hydroxyl, and M ^{1 is} Li, Na, K, MgCl, MgBr, MgI or Mgi / 2, the compound of the formula MIb being Isomer, Z-isomer or E / Z isomer mixture may be present

to a cis building block of the formula IVa or IVb,

optionally followed by the conversion of the triple bond into a double bond by reacting the Ci _{5 building} block of the formula IVa or IVb with a reducing agent, in particular with complex aluminum hydrides, to a cis building block of the formula IVa 'or IVb',

b) splitting off the protective groups of a cis-building block of the formulas IVa, IVb, IVa 'or IVb' by hydrolysis to give a deprotected cis building block of the formula Va or Vb,

followed by introduction of OH protecting groups which can be cleaved by hydrolysis to give a cis-ketone of formula VIa or VIb,

in which

Y -CH: = CH - or - c≡c is,

and

R ^{2 is} an ether, silyl ether or acetal protecting group convertible into a hydroxy group by hydrolysis,

c) reaction of a cis-ketone of the formula VIa or VIb by reduction of the carbonyl group to a secondary cis-alcohol of the formula VIIa or VIIb,

wherein Y and R ^{2 are} as defined in formula VIa in step b),

d) reaction of a secondary cis-alcohol of the formula VIIa or VIIb with a strong organic or inorganic acid HX and with a triarylphosphane P (aryl) 3, where X is the anion of the acid HX and aryl is a substituted or unsubstituted C6- Ci4-aryl radical, via a C15 phenol of the formula Villa or VIIIb as an isolable intermediate,

villa

wherein R ³ is OH or R ² , and R ² and Y are as defined in formula VIa in step b),

to a C 15-phosphonium salt of the formula IX or IX ',

wherein the Ci5-phosphonium salt of the formula IX 'by partial hydrogenation of the triple bond also IX is converted to the ₅ Ci -phosphonium salt of the formula,

e) Reaction of the cis-phosphonium salt of the formula IX with 2,7-dimethyl-octa-2,4,6-triene dial of the formula X.

in a double Wittig reaction to the compound of formula I,

where the compounds of the formulas IVb, IVb ', Vb, VIb, VIIb, VIIIb, XI and IX' can be present as E-isomer, Z-isomer or E / Z isomer mixture,

solved.

In the process according to the invention for preparing Φ, Φ-carotene-3,3'-diol, preference is given to at least step d), particularly preferably at least steps d) and e), in particular steps a), b), c) d ) and e).

In step a) of the process according to the invention, a monoketal of the formula II

wherein the radicals R ^{1 are} identical or different, in particular identical and are a Ci-Cs-, in particular Ci-C4-alkyl group, such as methyl, ethyl, n-propyl or n-butyl, or the two radicals R ¹ together for one divalent C2-C12, in particular are C 2 -C 8 -alkylene radical, that is to say, together with the atoms which join them, form a cyclic ketal, in particular a 5- or 6-ring ketal,

like for example

where R ⁴ , R ⁵ or R ⁶ independently of one another are hydrogen or C 1 -C ₄ -alkyl, such as methyl, ethyl, n-propyl or n-butyl, in particular the cyclic ketals

with a metalated alkyne of the formula IMa or IMb

preferably a metallated alkyne of the formula IIIa, where R ^{2 is} an ether, silyl ether or acetal protecting group which can be converted into a hydroxy group by hydrolysis, in particular for

and M ^{1 is} Li, Na, K, MgCl, MgBr, MgI or Mg / 2, in particular Li, Na, MgCl or MgBr, very particularly preferably Li, where the compound of the formula MIb is in the form of an E isomer, Z isomer or E / Z isomer mixture may be present

converted into a cis building block of the formula IVa or IVb, preferably IVa,

optionally followed by the conversion of the triple bond into a double bond by reacting the cis-building block of the formula IVa or IVb with a reductant onsmittel, in particular with complex aluminum hydrides, such as lithium aluminum hydride, diisobutylaluminum hydride and sodium bis (2-methoxyethoxy) - aluminum dihydride to a cis-building block of formula IVa 'or IVb', preferably IVa '

The monoketal of the formula II used in step a) can be prepared in known manner (Zh. Org. Khim. 26, 5, pp. 1087-1091, 1990. Engl. Translation pp. 936-940, 1990) from the known starting material 2, 3,5-trimethylbenzoquinone of the formula XI (Ullmanns Encyclopedia of Industrial Chemistry, Vol. A 27, p 485, 1969)

getting produced.

Preference is given in step a) to a cyclic monoketal of the formula II-a or II-b.

wherein R ⁴ , R ⁵ or R ⁶ independently of one another represent hydrogen or C 1 -C ₄ -alkyl, in particular the monoketals of the formulas II-a-1 or II-b-1

used.

The metallated alkynes of the formula IIIa and IIIb are obtainable from the known alkynes of the formulas IIIa-a (EP 633258) and IIIb-b (EP 5748),

Illa-a Illb-b in which R ^{2 is} an ether, silyl ether or acetal protecting group which can be converted by hydrolysis to a hydroxy group, preferably for

especially for

^{^} o ^{^} o

stands.

Preferably, in process step a), an alkyne of the formula IIIa-a is used.

The ethynylation of the carbonyl group in monoketals of the formula II-b-1 with propargyl alcohols is known in principle (Zh.Org.Khim., 27, 7, pp. 1423-1428, 1991, Engl., Compound pp. 1245-1249, 1992, Zh. Org. Khim. 26, 5, pp. 1087-1091, 1990; J. Org. Chem. USSR (Engl. Transl.) EN 26, 936-940, 1990).

Thus, the unprotected propargyl alcohol became 3-methyl-pent-4-en-1-yn-3-ol

llla-α-OH after metallation with 2 equivalents of ethyl magnesium bromide added to the monoketal of formula II-b-1. The formed diol of formula XIIa was obtained in a yield of 68% of theory (J. Org. Chem. USSR, EN 26, 936 et seq., 1990).

In an analogous manner, the primary propargyl alcohol became 3-methyl-pent-3-en-1-yn-5-ol of the formula IIIb-b-OH

IIIb-b-OH

converted into the diol of the formula XIIb in 38% yield (Zh. Org. Khim. 27, 7, pp. 1423 f., 1991, translation pp. 1245 f., 1992).

By hydrolysis of the ketal protecting group, the quinols of formulas Va-a and Vb-b were obtained from XIIa and XIIb.

In the process according to the invention, the use of protected propargyl alcohols of the formulas Illa-a or Illb-b in the alkynylation of monoketals of the formula II according to process step a) leads to significantly improved yields. Thus, the products of formulas IVa and IVb are obtained in this addition reaction in over 90% yield.

Preferably, in step a) the monoketal of the formula II-b-1 with the metallated alkyne of the formula MIa, wherein R ² is 0-CH (Me) -O-Et and M ¹ is Li, becomes the cis building block of the formula IVa in which the two radicals R ¹ together represent a divalent ethylene group and R ² is 0-CH (Me) -O-Et (compound of formula IVa-1).

To carry out the addition to a monoketal of the formula II, the alkynes of the formulas Illa-a and Illb-b are dissolved in an inert solvent such as, for example, gen or cyclic ethers or hydrocarbons by reaction with alkali or alkaline earth amides, hydrides, organolithium or Grignard reagents in the corresponding metalated alkynes of the formulas IMa or IMb transferred. Particularly preferred bases for the deprotonation of the alkyne are lithium amides or lithium organyls, here in particular butyllithium. The molar ratio of the alkyne of the formulas Illa-a or Illb-b to the monoketal of the formula II is usually between 1: 1 to 1.5: 1, preferably between 1.05: 1 and 1.3: 1. Excess alkyne can separated from IVa or IVb by distillation and recycled into the synthesis.

The conversion of the triple bond in the cis building block of the formula IVa or IVb into a double bond to a cis building block of the formula IVa 'or IVb' is carried out with the aid of a reducing agent. The reducing agents which can be used in principle are the complex aluminum hydrides described for the reduction of propargyl alcohols, in particular lithium aluminum hydride, diisobutylaluminum hydride and sodium bis (2-methoxyethoxy) aluminum dihydride (HeIv, Chim, Acta 73, 868, 1990). The reduction is carried out in inert cyclic or open-chain ethers (diethyl ether, methyl tert-butyl ether, THF) or open-chain or cyclic hydrocarbons, such as. For example, hexane or toluene.

The cis building block of the formula IVa-1 is particularly preferably converted into a cis building block of the formula IVa'-1

reduced.

In process step b), the protective groups of a cis building block of the formula IVa, IVb, IVa 'or IVb' are cleaved off by hydrolysis, in particular acid hydrolysis, to give a deprotected cis building block of the formula Va or Vb,

followed by the introduction of OH protecting groups, which can be split off by hydrolysis, to a C-ι ₅ -ketone of the formula VIa or VIb,

in which

Y - CH = CH - _O the - c≡c j _sti

and

R ^{2 is} an ether, silyl ether or acetal protecting group which can be converted by hydrolysis to a hydroxy group, preferably

especially for

"O ^' ~ o ^'

Both the hydrolysis of the protecting groups for the ketone function and the hydrolysis of the protected hydroxy functions in a cis building block of the formula IVa, IVb, IVa 'or IVb' to a deprotected cis building block of the formula Va or Vb is usually carried out in an inert solvent in the presence of water and catalytic amounts of a strong acid. Suitable solvents are water-miscible or immiscible inert solvents, such as open-chain or cyclic ethers, e.g. Diethyl ether, methyl tert-butyl ether, THF or dioxane, and hydrocarbons such as hexane, heptane, benzene, toluene or XyIoI and halogenated hydrocarbons such as methylene chloride, chloroform, 1, 2-dichloroethane, 1, 2-dichloropropane, chlorobenzene, etc. suitable , As acids, mineral acids such as sulfuric acid, hydrochloric or hydrobromic acid or phosphoric acid, and strong organic acids such as methane, benzenesulfonic or toluenesulfonic acid and formic acid, citric acid or trifluoroacetic acid can be used.

It was surprising to the person skilled in the art that in the case of a cis building block of the formula IVa 'or IVb' despite the absence of the C-C triple bond which has a stabilizing effect on the allyl alcohol grouping, no rearrangement or elimination occurs under the acidic reaction conditions.

Particularly preferably, the cis building block of the formula IVa'-1 is deprotected to the Ci _{5 building} block of the formula Va'-a.

The protection of the free OH groups in the cis building block of the formula Va or Vb leads to the Ci ₅ -ketone of the formula VIa or VIb.

The introduction of the protective groups is carried out by methods known from the literature (see, for example, H. Stalder, Methods of Synthesis of Organic Chemistry, Separate Print of the Swiss Laboratory Magazine, 1st Edition, Copyright 1978).

Preferably, a deprotected cis-building block of the formula Va is converted by addition of two equivalents of vinyl ethyl ether into a cis-ketone of the formula VIa,

wherein Y is -CH = CH - or - c≡c, and

R ^{2 is} -O-CH (Me) -O-CH ₂ CH ₃ .

In process step c), a cis-ketone of the formula VIa or VIb is converted by reduction of the carbonyl group to a secondary cis-alcohol of the formula VIIa or VIIb,

wherein Y and R ^{2 are} as defined in formula VIa in step b).

For this step, in principle, all hydride reducing agents are suitable with which a keto group can be reduced to the alcohol, such as complex boron and aluminum hydrides such. Sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride or sodium bis (2-methoxyethoxy) aluminum dihydride.

Particularly preferably, a cis-ketone of the formula VIa is converted by reduction into a secondary cis-alcohol of the formula VIIa,

wherein

Y -CH ^: = CH - or - c≡c- is, and

R ^{2 is} -O-CH (Me) -O-CH ₂ CH ₃ .

In the process according to the invention for the preparation of Φ, Φ-carotene-3,3'-diol, the cis-ketone of the formula VIa and VIb prepared in process step b is preferred without isolation and without further workup in process step c) for the preparation of the secondary cis Alcohol of formula VIIa or VIIb used.

In process step d), the reaction of a secondary cis-alcohol of the formula VIIa or VIIb with a strong organic or inorganic acid HX and with a triarylphosphane P (aryl) 3, wherein X represents the anion of the acid HX and aryl is a substituted or unsubstituted C6-Ci4-aryl radical, via a cis-phenol of the formula Villa or VIIIb as an isolable intermediate,

to a C 15-phosphonium salt of the formula IX or IX ',

wherein the Ci5-phosphonium salt of formula IX 'is also converted by partial hydrogenation of the triple bond in the cis-phosphonium salt of formula IX.

For aromatization, a secondary cis-alcohol of the formula VIIa or VIIb is subjected to the reaction conditions of the OH-protecting group elimination, in particular the acid-catalyzed acetal hydrolysis.

Strong organic or inorganic acids are understood as meaning those acids whose pK _a values are less than 3, preferably less than 1. Examples of strong organizational see or inorganic acids are hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid, or trihaloacetic acids, such as trifluoroacetic acid or trichloroacetic acid.

In the triarylphosphane P (aryl) ₃ , the aryl radicals are both substituted and unsubstituted Cβ-Cu, preferably Cδ-Cio-aryl radicals, in particular phenyl. The substituents on the aryl radical can be, for example, halogens and / or C 1 -C 12, in particular C 1 -C 4 -alkyl radicals, such as methyl, ethyl, propyl or butyl. In process step d), triphenylphosphane is preferably used as the triarylphosphane P (aryl) 3.

The acid-catalyzed aromatization of a quinol system to the phenol ring is known in principle (Zh.Org.Khim., 27, 12, 2588 f., 1991. Translation pp 2305 f, 1992). In the literature, however, the free tertiary alcohol on the ring and not its protected form, such as the acetal was assumed. In addition, the substrate contained no further allylic alcohol or acetal groups.

Aromatization according to Zh. Org. Khim. 27, 12, 2588 f.

In the treatment of secondary cis-alcohol of formula VIIa or VIIb, in particular of a secondary alcohol of the formula VIIa Ci _5, wherein R ² is -O-CH (Me) -O-CH2CH3 group, under the conditions of the acid-catalyzed acetone The allylic alcohol functions remain intact. This result is surprising because the skilled person would have expected dehydration or rearrangements also at the second allylic OH group.

It is particularly surprising that in the presence of strong acid and triphenylphosphane, i. under conditions of phosphonium salt formation, starting from a secondary C 15 -alcohol of the formula VIIa or VIIb can be achieved directly in one step to a phosphonium salt of the formula IX or IX ', wherein an isolable intermediate of the formula Villa or VIIIb is run through.

Hydrobromic acid or hydrochloric acid and triphenylphosphine as triarylphosphane P (aryl) 3 are preferably used in process step d) in the reaction of the secondary cis-alcohol of the formula VIII or VIIIb to give the cis-phosphonium salt of the formula IX or IX '. As preferred reagent for the direct conversion of a secondary cis-alcohol of the formula VIIa or VIIb into a cis-phosphonium salt of the formula IX or IX ', triarylphosphine-HX adducts of the formula P (aryl) 3 ^* HX, in particular triphenylphosphine hydrochloride or triphenylphosphine hydrobromide used.

In a particularly preferred embodiment of process step d), the secondary cis-alcohol of the formula VIIa,

wherein

Y is ^{^-CH:} CH - or -C≡C-, and

R ² for -O-CH (Me) -O-CH ² CH 3 is reacted with triphenylphosphine hydrobromide to give a cis-phosphonium salt of the formula IX or IX '. In this case, as intermediates, the Ci5 phenols of the formula VIIIa and VIIa-b run through, but need not be isolated in substance.

in which

Y is -CH ^: = CH - or -c≡c- is, and

Aryl is phenyl and X is Br.

The partial hydrogenation of the C-C triple bond in the acetylenic phosphonium salt of the formula IX 'to the phosphonium salt of the formula IX is carried out as described in the literature (EP 100 839).

Preferably, in process step d) of the process according to the invention for the production of Φ, Φ-carotene-3,3'-diol, the intermediate of the formula VIIIa or VIIIb is not isolated, but the secondary cis-alcohol of the formula VIIa or VIIb directly to the cis Phosphonium salt of the formula IX or IX 'implemented. The compounds of the formulas IVb, IVb ', Vb, VIb, VIIb, VIIIb, XI and IX' used or obtained in process steps a), b), c), d) and e) can be used as E isomer, Z, Isomer or E / Z isomer mixture present.

In process step e), the reaction of the cis-phosphonium salt of the formula IX with 2,7-dimethyl-octa-2,4,6-trienienially reacted in a double Wittig reaction to the compound of formula I.

The double Wittig condensation of the cis-phosphonium salt of the formula IX with 2,7-dimethyl-octa-2,4,6-triene-1,8-dial of the formula X, which is not described in the literature, can be carried out under the conditions for this process in principle, methods known from the literature (see "Carotenoids, Vol 2: Synthesis", Birkhäuser Verlag, 1996. Preferred bases for the production of the ylid are alkali metal or alkaline earth metal C 1 -C 6 -alcoholates, preferably as a solution in the corresponding C 1 -C 6 As the solvent, chlorinated hydrocarbons such as methylene chloride, 1, 2-dichloroethane, 1, 2-dichloropropane or open-chain or cyclic ethers can be used.As ethereal solvents, for example, tetrahydrofuran, dioxane or ethers of ethylene glycol can be used. It is also possible to use hydroxyl-containing ethers, such as 1-methoxy-2-propanol or 1-methoxy-2-propanol, or else the C 1 -C 6 -hydric alcohol corresponding to the alkoxide, either alone or in combination t one of the above-mentioned solvents - suitable for this reaction.

Another preferred embodiment consists in the generation of the ylide by oxiranes as "latent bases" (Chem. Ber 107, 2050 ff, (1974)), for example by heating the C 15-phosphonium salt of the formula IX in the presence for several hours of the dialdehyde of the formula X in an oxirane as solvent, preferably 1,2-epoxybutane This reaction can be carried out in pure oxirane or in mixtures of the oxirane with one of the abovementioned solvents The end product of the formula I can be obtained by filtration of the reaction mixture without additional Work-up steps are isolated.

In the formulas 1 and 2, some process steps of the above-described process for the preparation of Φ, Φ-carotene-3,3'-diol of the formula I are illustrated by two concrete examples. Scheme 1

VILIA-OH

Scheme 2

While in Scheme 1 the selective hydrogenation of the C-C triple bond occurs only after the preparation of the cis-phosphonium salt of formula IX ', in Scheme 2 the C-C triple bond is selectively reduced to the C-C double bond immediately after the alkynylation of the monoketal of formula II. A further subject of the present invention is a cis building block of the formula IVa or IVb,

wherein the radicals R ¹ and R ² are defined as described above in step a), that is to say in which R ^{1 are} identical or different, in particular identical and are a C ¹ -C 8 -alkyl group, or the two radicals R ¹ together represent a bicyclic C ₂ -C 12 -alkylene radical, that is to say, together with the atoms which join them, form a cyclic ketal, in particular a 5- or 6-ring ketal, and R ^{2 represents} an ether which can be converted into a hydroxy group by hydrolysis. , Silyl ether or acetal protecting group, and wherein the cis-building block of the formula IVb can be present as E-isomer, Z-isomer or E / Z isomer mixture.

Particularly preferred is a cis-building block of the formula IVa, the same

is.

Likewise provided by the present invention is a cis building block of the formula IVa 'or IVb',

wherein the radicals R ¹ and R ² are defined as described above in step a), that is to say in which R ^{1 are} identical or different, in particular different and are a C ¹ -C 8 -alkyl group or the two radicals R ¹ together represent a divalent C 2 -C 12 -alkylene radical, that is to say, together with the atoms which join them, form a cyclic ketal, in particular a 5- or 6-ring ketal, and R ² denotes an ether, silyl radical which can be converted into a hydroxy group by hydrolysis. ether or acetal protecting group, and wherein the cis-building block of formula IVb 'may be present as E-isomer, Z-isomer or E / Z isomer mixture.

Particularly preferred is a cis-building block of the formula IVa ', the same

is.

In addition, the cis building block of the formula Va'-a

Another object of the present invention.

Likewise provided by the present invention is a cis-ketone of the formula VIa or VIb,

wherein Y and the radical R ² are defined as previously described in step b), that is, wherein Y is -CH = CH- or a CC triple bond and R ^{2 is} an ether convertible by hydrolysis to a hydroxy group , Silylether- or acetal protecting group, and wherein the cis-ketone of the formula VIb may be present as E-isomer, Z-isomer or E / Z isomer mixture.

Particularly preferred is a cis-ketone of formula VIa wherein Y is -CH = CH- or a CC triple bond and R ² is -Q-CH (Me) -O-CH ₂ CH ₃ . Another object of the present invention is a secondary cis-alcohol of the formula VIIa or VIIb

wherein Y and R ^{2 are} also defined as in the cis-ketones of the formula VIa or VIb, that is to say in which Y is -CH =CH- or a C-C triple bond and R ^{2 is} an ether, which can be converted into a hydroxy group by hydrolysis, Silyl ether or acetal protecting group, and wherein the secondary cis-alcohol of the formula VIIb may be present as E-isomer, Z-isomer or E / Z isomer mixture.

Particularly preferred is a secondary cis-alcohol of formula VIIa wherein R ² is -O-CH (Me) -O-CH ₂ CH ₃ .

A Ci ₅ phenol of the formula VIIIa or VIIIb is also the subject of the present invention.

VIIIb

wherein R ³ is OH or R ² , and R ² and Y are as in formula VIIa, and wherein the Ci5-phenol of formula VIIIb may be present as E-isomer, Z-isomer or E / Z isomer mixture.

Preferred is a cis-phenol of formula Villa wherein R ³ is OH or -O-CH (Me) -O-CH ₂ CH ₃ . Likewise provided by the present invention is a cis-phosphonium salt of the formula IX or IX '

wherein aryl and X are defined as previously described in step d), that is, wherein X is the anion of a strong organic or inorganic acid HX, and aryl is a substituted or unsubstituted C6-Ci4 aryl radical, and wherein the C15 phosphonium salt of the formula IX or IX 'can be present as E isomer, Z isomer or E / Z isomer mixture.

Preferably, X is Cl or Br and aryl is phenyl.

Another object of the present invention is also a process for the preparation of a phosphonium salt of the formula IX

characterized in that a secondary cis-alcohol of the formula VIIa or VIIb

wherein

Y is - CH = CH - or - c≡c,

R ^{2 is} an ether, silyl ether or acetal protecting group which can be converted by hydrolysis into a hydroxy group, and where the secondary cis-alcohol of the formula VIIb can be present as E-isomer, Z-isomer or E / Z isomer mixture, with a strong organic or inorganic acid HX and with a triarylphosphane P (aryl) 3, where X represents the anion of the acid HX and in particular represents Cl or Br, and aryl represents a substituted or unsubstituted C6-Ci ₄ -aryl radical , in particular phenyl, stands,

is converted to a Ci5-phosphonium salt, wherein in the case of a starting material of the formula VIIa or VIIb, in which Y represents a triple bond, the triple bond of this cis-phosphonium salt is converted by partial hydrogenation in a double bond to the Ci5-phosphonium salt of the formula IX go, wherein the cis-phosphonium salt of formula IX may be present as E-isomer, Z-isomer or E / Z isomer mixture.

The invention is illustrated by the following, but not limiting examples of the invention.

General information: The production and handling of the organometallic compounds was carried out under exclusion of air and moisture under inert gas.

Example 1 - Synthesis of the cis building block of the formula IVa-1

165.4 g (0.961 mol) of the alkyne of the formula IIIa-a-1 in 1.8 l of toluene were dissolved in two parallel batches. At 0 ° C was added dropwise 335 ml of a 2.5 molar solution of n-butyllithium in hexane (= 0.886 mol BuLi) and stirred for 30 minutes at 0 ° C after. Subsequently, a solution of 143.5 g (0.739 mol) of the monoketal of the formula II-b-1 in 370 ml of toluene was added dropwise and stirred for 1 h at 0 ° C after. For workup, 370 ml of ice water were run. It was stirred well for 5 minutes and combined both approaches in a separatory funnel. The lower phase was separated and the upper phase washed twice with 370 ml of 10% aqueous acetic acid and water. The upper phase was dried with sodium sulfate. After filtering off the drying agent, the filtrate was concentrated on a rotary evaporator at 60 ° C. to 10 mbar. Excess alkyne was separated by vacuum distillation on a thin film evaporator at 100 ° C heating temperature and a vacuum of 5-6 mbar. 513.4 g of the cis building block of the formula IVa-1 were obtained as the effluent of the thin-film evaporator; this corresponded to a yield of 96% Th. (based on ll-b-1). The product had a purity of 97.7% by gas chromatographic analysis. Example 2 - Synthesis of the cis building block of the formula Va-a

359 g (0.989 mol) of the cis building block of the formula IVa-1 (97.7% strength) from Example 1 were dissolved in 990 ml of tetrahydrofuran. Subsequently, 178 g (9.89 mol) of water and 23.53 g of a 40% aqueous solution of p-toluenesulfonic acid monohydrate (= 49.5 mmol, p-toluenesulfonic acid) were added at 20-25 ° C. The mixture was stirred at + 50 ° C for 1 h. For workup, the mixture was diluted with 5 l of methyl tert-butyl ether. The organic phase was washed once with 1 l of saturated bicarbonate solution and twice with 1 l of water each time and dried with sodium sulfate. After filtering off the desiccant, the filtrate was concentrated on a rotary evaporator at 50 ° C to 20 mbar. 236.6 g of the cis building block of the formula Va-a (97.3% of theory) having a purity of 99.1% (gas chromatographic) were obtained as residue. For purification, the product was recrystallized from 500 ml of toluene.

There were obtained 216 g of the cis-building block of the formula Va-a with a gas chromatographic see purity of 100% and a melting point of 106.5 - 107 ° C.

Example 3 - Synthesis of cis-ketone of formula Vla-1

189.6 g (0.77 mol) of the cis building block of the formula Va-a from Example 2 were suspended in 1, 44 l of toluene. 1.10 g (5.78 mmol) of p-toluenesulfonic acid monohydrate were added and then 208.4 g (2.89 mol) of vinyl ethyl ether were added dropwise over 30 minutes at 20-25 ° C. After stirring for a further 30 minutes, 550 mg (2.89 mmol) of para-toluenesulfonic acid monohydrate were again added and the mixture was stirred at room temperature for a further 3 hours. For working up, 190 ml of saturated bicarbonate solution were added and the mixture was stirred vigorously for 5 minutes. The aqueous lower phase was separated and the organic upper phase washed once with 190 ml of saturated sodium bicarbonate solution and twice with 80 ml of water. The organic phase was dried with sodium sulfate. After filtering off the drying agent, the filtrate was concentrated on a rotary evaporator at 50 ° C to 5 mbar. 305.3 g of the cis-ketone of the formula Vla-1 were obtained as residue, which was further processed as crude product without further purification. The raw yield was quantitative. Example 4 - Synthesis of the secondary cis-alcohol of formula VIIa-1

VIIa 1

In two parallel batches each 152.6 g (0.385 mol telquel) of the crude C15 ketone of the formula Vla-1 from Example 3 were dissolved at room temperature in 1540 ml of THF. At 0 ° C was allowed within 60 minutes, 120 g of a 65% toluene solution of sodium bis (2-methoxyethoxy) -aluminum dihydride, which was diluted with 1540 ml of toluene, run. The mixture was stirred for 1 hour at 0 ° C after. Then added dropwise at 0 ° C, a mixture of 77 ml of ethanol and 77 ml of hexane, stirred for 15 minutes at 0 ° C, added dropwise at 0 ° C 77 ml of 15% sodium hydroxide solution and stirred again for 15 minutes at 0 ° C after , The mixture was added at 0 ° C with 144 ml of water; The mixture was allowed to warm to room temperature and 320 ml of n-hexane were added. The biphasic mixture was then transferred to a separatory funnel. The lower phase was separated, the upper phase washed three times with 77 ml of half-concentrated saline. The combined lower phases were once again extracted with toluene. The organic upper phases of both batches were combined, dried with sodium sulfate and concentrated on a rotary evaporator at + 60 ° C to 5 mbar. 322.9 g of crude secondary cis-alcohol of the formula VIIa-1 were obtained as residue. Purity by HPLC 86.2%; this corresponded to a yield of 92.2% of theory, based on the cis-building block of the formula Va-a.

Example 5 - Synthesis of the cis-phenol of the formula VIIIa-1

VIIIa-1

49.1 g of the crude secondary cis-alcohol of the formula VIIa-1 from Example 4 (86.2% strength = 0.108 mol) were dissolved in 500 ml of tetrahydrofuran. 2.63 g (12.5 mmol) of citric acid monohydrate were added and the mixture was heated at reflux for 7 hours. Then allowed to cool to room temperature, diluted with 500 ml of n-hexane and washed twice with 150 ml of saturated sodium bicarbonate solution and once with 150 ml of half-concentrated saline. The combined washing phases were back-extracted once with 150 ml of n-hexane. The organic phases were combined, dried with sodium sulfate and concentrated on a rotary evaporator at + 50 ° C to 10 mbar. 39.5 g of the crude cis-phenol of the formula VIIIa-I were obtained as a yellow oil having a purity of 88.3% by HPLC (quantitative yield). Example 6 Synthesis of the C15 Phosphonium Salt of Formula IX '

IX ¹

a) from the cis-phenol of the formula VIIIa-1

1.51 g of the cis-phenol of the formula VIIIa-1 from Example 5 (88.3% strength = 4.42 mmol) were dissolved in 10 ml of methylene chloride. At 0 ° C was added dropwise to a solution of 1, 56 g (4.5 mmol) of triphenylphosphine hydrobromide in 18 ml of methylene chloride and stirred for 1 h at 0 ° C and a further hour at room temperature. Then the mixture was concentrated on a rotary evaporator at + 50 ° C to 5 mbar. 2.65 g of crude phosphonium salt of the formula IX 'were obtained as residue. For crystallization, the residue was taken up in 20 ml of acetonitrile. The mixture was heated under reflux for 15 min, cooled and stirred for 1 hour at 0 ° C after. The crystals were filtered off, washed with a little cold acetonitrile and dried at + 50 ° C / 20 mbar.

Weight: 1.21 g of C15 phosphonium salt of the formula IX '(49.3% of theory) mp: 222.5-223 ° C. purity by HPLC: 98.8%

The filtrate was concentrated on a rotary evaporator at + 50 ° C to 20 mbar. The residue obtained was 1.24 g of light brown viscous oil containing 39.9% of C15-phosphonium salt of the formula IX '(according to HPLC).

b) from the secondary Ci ₅ -alcohol of formula VIIa-1

39.2 g of the secondary cis-alcohol of the formula VIIa-1 from Example 4 (purity 86.2%, = 86.6 mmol) were dissolved in 200 ml of methylene chloride. Within 1 hour, added dropwise at 0 ° C, a solution of 31, 2 g of triphenylphosphine hydrobromide in 180 ml of methylene chloride. The mixture was stirred for 1 hour at 0 ° C. and for a further 1 hour at room temperature. For crystallization of the phosphonium salt, the solvent was distilled off under simultaneous feed of 500 ml of acetonitrile under atmospheric pressure until a transition temperature of + 80 ° C was reached.

The resulting suspension was cooled to 0 ° C, stirred for 1 hour at 0 ° C and the product was filtered off. The filter cake was washed with a little cold acetonitrile and dried at + 50 ° C / 20 mbar.

Weighing: 17.3 g of the C15 phosphonium salt of the formula IX '(36.0% of theory) Purity by HPLC: 96.7% mp: 218.5-219 ° C

The filtrate was concentrated on a rotary evaporator at + 50 ° C to 20 mbar. The residue was taken up in 100 ml of acetonitrile. The mixture was stirred for 15 min at +70 ⁰ C, cooled to 0 ° C and stirred at 0 ° C for 1 hour. The secondary crystals were filtered off, washed with a little cold acetonitrile and dried at + 50 ° C / 20 mbar.

Dye: 17.4 g of C15 phosphonium salt of formula IX '(36.2% of theory). Purity by HPLC: 99.4% overall yield of C15 phosphonium salt of formula IX': 72.2% of theory. Th.

The filtrate of the secondary crystals was evaporated on a rotary evaporator at + 50 ° C to 20 mbar. This gave 18.0 g of foamy material containing 21.1% (according to HPLC) of C15-phosphonium salt of the formula IX '.

Example 7 - Synthesis of the cis-phenol of the formula

1.96 g of the crude secondary cis-alcohol of the formula VIIa-1 from Example 4 (86.2%; = 4.31 mmol) were dissolved in 10 ml of tetrahydrofuran. 0.9 g of water (50 mmol) and 240 mg of citric acid monohydrate were added and then heated under reflux for 5 h. The mixture was allowed to cool to room temperature, diluted with 25 ml of methyl tert-butyl ether and washed once with 5 ml of saturated sodium bicarbonate solution and twice with 5 ml of water. The organic phase was dried with sodium sulfate and concentrated on a rotary evaporator at + 50 ° C to 10 mbar.

0.87 g of a high-viscosity yellow oil was obtained which crystallized on standing. Content of Ci ₅ -phenol of the formula VIIIa-OH according to HPLC: 65.4%; this corresponds to a yield of cis-phenol of formula VIIIa-OH of 57.4% d. Th. For characterization, the crude product was dissolved in 4 ml of toluene in the heat; it was allowed to cool to 0 ° C and stand at 0 ° C for 1 hour. The crystals were filtered off, washed with a little cold toluene and dried at 50 ° C / 20 mbar.

Weight: 190 mg of the C-15 phenol of the formula VIIIa-OH mp: 132-134 ° C. Purity by HPLC: 94.8% Example 8 - Synthesis of the cis-building block of the formula IVa'-1

36.3 g of Ci5 building block of the formula IVa-1 (97.7% strength) from Example 1 (97.7% pure by GC analysis, = 0.098 mol) were dissolved in 400 ml of tetrahydrofuran. At 0 ° C., 62.2 g of sodium bis (2-methoxyethoxy) aluminum dihydride (65% in toluene, diluted with 400 ml of toluene) were allowed to run in over the course of 1 hour. The mixture was stirred for 2 hours at 0 ° C after. For workup, a mixture of 33 ml of ethanol and 33 ml of n-hexane and then 33 ml of 15% sodium hydroxide solution were added dropwise at 0 ° C first. Then, 65 ml of water was added. It was allowed to come to room temperature, added to 140 ml of n-hexane and the aqueous subphase separated. The organic phase was washed three times with 40 ml semisaturated saline. The combined phases were reextracted once with 40 ml of toluene. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator at + 60 ° C to 5 mbar. The residue obtained was 36.5 g of a yellow viscous oil containing 88.6% of the cis building block of the formula IVa'-1 according to GC analysis. This corresponded to a yield of 90.7% d. Th.

Example 9 - Synthesis of the cis building block of the formula Va'-a

36.3 g of the crude cis building block of the formula IVa'-1 from Example 8 (88.6% strength = 88.4 mmol) were dissolved in 100 ml of tetrahydrofuran. 18 g of water and 2.15 g of a 40% aqueous solution of p-toluenesulfonic acid monohydrate (= 5.0 mmol of p-toluenesulfonic acid) were added and the mixture was stirred at room temperature for 1 hour. For workup, the batch was diluted with 500 ml of methyl tert-butyl ether. It was washed once with 100 ml of saturated sodium bicarbonate solution and twice with 100 ml of water, dried with sodium sulfate and concentrated on a rotary evaporator at + 60 ° C to 20 mbar. The residue obtained was 24.8 g of the crude cis building block of the formula Va'-a as a beige solid with a purity of 90.6% by GC analysis. This corresponded to a quantitative yield.

For characterization, the crude compound of the formula Va'-a was dissolved in the heat in 150 ml of toluene. The white solution was clear filtered through a paint filter and cooled to 0 ° C. The resulting suspension was stirred for 1 hour at 0 ° C and filtered. The filter cake was washed with a little cold toluene and dried at 50 ° C / 20 mbar. Weight obtained: 15.7 g (99.1% pure according to GC analysis), mp 139-140 ⁰ C.

Example 10 - Synthesis of cis-ketone of formula Vla'-1

14.9 g (60.1 mmol) of crystallized product of the formula Va'-a from Example 9 were suspended in 110 ml of toluene. At room temperature, 173 mg (0.9 mmol) of p-toluenesulfonic acid monohydrate were added. Then, 21, 7 g (300 mmol) of vinyl ethyl ether were run in, the temperature of the mixture was raised to + 50 ° C and stirred for 2 h at + 50 ° C after. The mixture was cooled to room temperature, 15 ml of saturated sodium bicarbonate solution were added and the mixture was stirred vigorously for 5 minutes. The aqueous lower phase was separated and the organic upper phase washed once with 15 ml of saturated sodium bicarbonate solution and twice with 6 ml of water, dried with sodium sulfate and concentrated on a rotary evaporator at + 60 ° C to 1 mbar. This gave 22.5 g of the cis-ketone of formula Vla'-1 (crude yield 94.1%) as a yellow oil.

Example 11 - Synthesis of the secondary cis-alcohol of formula VIIa'-1

22.3 g of the crude cis-ketone of the formula Vla'-1 from Example 10 (56.9 mmol of telquel) were dissolved in 230 ml of tetrahydrofuran. At 0 ° C was allowed within 1 hour 17.7 g of sodium bis (2-methoxethoxy) -aluminiumdihydrid (65% in toluene), diluted with 230 ml of toluene, run. The mixture was stirred for 1 h at 0 ° C and then allowed to run first a mixture of 11 ml of ethanol and 11 ml of hexane and then 11 ml of 15% sodium hydroxide solution. The mixture was stirred for 15 min at 0 ° C, 22 ml of water and 40 ml of n-hexane and allowed to come to room temperature. The aqueous lower phase was separated and the organic upper phase washed three times with 11 ml of half-saturated saline solution. The aqueous phases were combined and extracted once with 11 ml of toluene. The combined organic phases were dried with sodium sulfate and concentrated on a rotary evaporator at + 60 ° C to 1 mbar. 23.8 g of the crude secondary cis-alcohol of formula VIIa'-1 were obtained as a viscous light brown oil. Example 12 - Synthesis of the C15 Phosphonium Salt of Formula IX

20.5 g of the crude secondary cis-alcohol of formula VIIa'-1 (52.0 mmol of telquel) from example 11 was dissolved in 105 ml of methylene chloride. Within 1 hour, added dropwise at 0 ° C, a solution of 16.25 g (46.9 mmol) of triphenylphosphine hydrobromide in 95 ml of methylene chloride. The mixture was allowed to come to room temperature and then heated under reflux for 2 hours. Then the solvent was removed on a rotary evaporator at + 50 ° C to 5 mbar. This gave 28.5 g of an ocher-colored solid which, according to HPLC analysis, contains 68.9% phosphonium salt of the formula IX. This corresponds to a yield of about 66% d. Th, based on the cis building block of the formula Va'-a. The crude product was taken up in 100 ml of acetone. By adding 200 ml of ethyl acetate, the phosphonium salt of formula IX was precipitated. The solid was separated and dried at + 50 ° C / 20 mbar.

Weighing: 15.4 g mp: 234-235 ° C

Example 13 Synthesis of 3,3'-Dihydroxyisorenieratin in Formula I,

136.8 g (0.248 mol) of the C15-phosphonium salt of the formula IX prepared according to Example 12 were suspended at room temperature in 560 ml of ethanol. Subsequently, 18.5 g (0.113 mol) of 2,7-dimethyl-octa-2,4,6-trienes of the formula X were

and 170 ml of 1,2-epoxybutane added. The mixture was refluxed for 20 hours. The resulting suspension was cooled to 0 ° C. and stirred at 0 ° C. for 1 hour. The precipitate was filtered off and the filter cake washed twice with 100 ml of ethanol at 0 ° C. For high purification, the wet filter cake was taken up in 600 ml of tetrahydrofuran. The suspension was heated to reflux and refluxed for 30 minutes. The mixture was filtered hot; Subsequently, 350 ml of solvent were distilled off and simultaneously 750 ml of acetonitrile were added dropwise. The crystal suspension was refluxed for 20 hours. Then the suspension was cooled to room temperature, stirred for 1 hour and filtered off. The filter cake was washed twice with 50 ml of acetonitrile and dried at 50 ° C / 20 mbar.

(. 61, 5% of theory.): Weight 38.9 g, mp 228-230 ⁰ C.

HPLC: 98.9% purity E ¹ i (CHCl ₃ ): 2176 at 465 nm

Claims

claims

1. A process for the preparation of 3,3'-dihydroxyisorenieratin in the formula I,

comprising at least one of the steps:

a) Reaction of a monoketal of the formula II

in which the radicals R ^{1 are} identical or different and are a C 1 -C 5 -alkyl group, or the two radicals R ¹ together represent a bivalent C2-C 12 -alkylene radical, that is, together with the atoms which connect them, a cyclic ketal form,

with a metalated alkyne of the formula IMa or IMb

to a cis building block of the formula IVa or IVb,

optionally followed by the conversion of the triple bond into a double bond by reacting the cis building block of the formula IVa or IVb with a reducing agent to give a cis building block of the formula IVa 'or IVb',

in which

Y is -CH = = CH - or - c≡c,

and

R ^{2 is} an ether, silyl ether or acetal protecting group convertible by hydrolysis to a hydroxy group,

wherein Y and R ^{2 are} as defined in formula VIa in step b),

d) reacting a secondary cis-alcohol of the formula VIIa or VIIb with a strong organic or inorganic acid HX and with a triarylphosphane P (aryl) 3, where X represents the anion of the acid HX and aryl represents a substituted or unsubstituted C6-C14 Arylrest, via a Ci ₅ phenol of the formula Villa or VIIIb as an isolable intermediate,

to a C 15-phosphonium salt of the formula IX or IX ',

where the C 15-phosphonium salt of the formula IX 'is likewise converted into the C 15-phosphonium salt of the formula IX by partial hydrogenation of the triple bond,

in a double Wittig reaction to the compound of formula I,

wherein the compounds of the formulas IVb, IVb ', Vb, VIb, VIIb, VIIIb, XI and IX' can be present as E-isomer, Z-isomer or E / Z isomer mixture.

2. The method according to claim 1, characterized in that at least the steps d) and e) are performed.

3. The method according to claim 1 or 2, characterized in that the prepared in step b) cis-ketone of the formula VIa and VIb used without isolation and without further work-up in step c) for the preparation of the secondary Ci5-alcohol of the formula VIIa or VIIb becomes.

4. The method according to any one of claims 1 to 3, characterized in that in process step d) for the reaction of the secondary cis-alcohol of formula VIIa or VIIb to cis-phosphonium salt of formula IX or IX 'as a strong acid HX hydrobromic acid or hydrochloric acid and triphenylphosphine is used as triarylphosphane P (aryl) 3.

5. The method according to any one of claims 1 to 4, characterized in that in step d) the intermediate of the formula Villa or VIIIb is not isolated, but the secondary cis-alcohol of formula VIIa or VIIb directly to the cis-phosphonium salt of formula IX or IX 'is implemented.

6. Ci5 building block of the formula IVa or IVb,

wherein

R ^{1 are} identical or different and are a C ¹ -C 5 -alkyl group or the two R ¹ radicals together represent a bivalent C 2 -C 12 -alkylene radical, that is to say, together with the atoms which join them, form a cyclic ketal, and

R ^{2 is} an ether, silyl ether or acetal protecting group convertible by hydrolysis to a hydroxy group, and

wherein the cis-building block of formula IVb may be present as E-isomer, Z-isomer or E / Z isomer mixture.

7. Ci5 building block according to claim 6, wherein formula IVa is the same

is.

8. Cis building block of the formula IVa 'or IVb',

wherein

R ^{1 are} identical or different and are a Ci-Cs-alkyl group or the two radicals R ¹ together represent a divalent C2-Ci ₂ alkylene, that is, together with the atoms connecting them form a cyclic ketal, and

wherein the cis-building block of the formula IVb 'may be present as E-isomer, Z-isomer or E / Z isomer mixture.

A cis building block according to claim 8, wherein formula IVa 'is the same

is.

10. Cis building block of the formula Va'-a

1 1. Ci5 ketone of the formula VIa or VIb,

wherein

Y is CH ^ CH - or - c≡c,

and

wherein the cis-ketone of the formula VIb can be present as E-isomer, Z-isomer or E / Z isomer mixture.

12. cis-ketone of the formula VIa according to claim 1 1,

wherein

Y is - CH ^ CH- or -c≡c-,

and

R ^{2 is} -O-CH (Me) -O-CH ₂ CH ₃ .

13. Secondary cis-alcohol of formula VIIa or VIIb

wherein

Y is - CH ^ CH- or -c≡c-,

and R ^{2 is} an ether, silyl ether or acetal protecting group convertible by hydrolysis to a hydroxy group, and

wherein the secondary Ci ₅ -alcohol of formula VIIb may be present as E-isomer, Z-isomer or E / Z isomer mixture.

14. Secondary cis-alcohol of formula VIIa according to claim 12,

wherein

R ² is -O-CH (Me) -O-CH ₂ CH ₃ .

15. Cis-phenol of formula Villa or VIIIb

wherein R ³ is OH or R ² , and R ² and Y are as defined in formula VIIa according to claim 13, and

wherein the cis-phenol of the formula VIIIb may be present as E-isomer, Z-isomer or E / Z isomer mixture.

16. Cis-phenol of the formula Villa according to claim 15,

wherein

R ³ is OH or -O-CH (Me) -O-CH ₂ CH ₃ .

17. Ci5 phosphonium salt of the formula IX or IX '

wherein

X is the anion of a strong organic or inorganic acid HX and aryl is a substituted or unsubstituted C6-Ci4 aryl radical, and

where the C15 phosphonium salt of the formula IX or IX 'can be present as E isomer, Z isomer or E / Z isomer mixture.

18. A process for the preparation of a phosphonium salt of the formula IX

characterized in that a secondary cis-alcohol of the formula VIIa or VIIb

wherein

Y is - CH ^ CH - or - c≡C-,

R ^{2 is} an ether, which can be converted into a hydroxy group by hydrolysis,

Silyl ether or acetal protecting group, and wherein the secondary cis-alcohol of the formula VIIb can be present as E-isomer, Z-isomer or E / Z isomer mixture, with a strong organic or inorganic acid HX and with a triarylphosphane P (aryl) 3, where X represents the anion of the acid HX and aryl represents a substituted or unsubstituted C 6 -C 14 aryl radical,

is converted to a cis-phosphonium salt, wherein in the case of a starting compound of the formula VIIa or VIIb in which Y represents a triple bond, the triple bond of this cis-phosphonium salt is converted by partial hydrogenation into a double bond to the cis-phosphonium salt of the formula IX reach, wherein the cis-phosphonium salt of formula IX may be present as E-isomer, Z-isomer or E / Z isomer mixture.