TW200811095A - Method for producing 3,3'-dihydroxyisorenieratine and also novel intermediates therefor - Google Patents

Abstract

The present invention relates to a novel method for producing 3,3'-dihydroxyisorenieratine of the formula I, and also intermediates of this method.

Description

200811095 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a method for preparing a dihydroxyisohexadiene which is a basic dimethyl group (3,3-<1111}^(11*〇父丫A novel method of 18 〇 1116^{61^) (hereinafter referred to as 0,(1)-carotene-3,3'-diol), and also relates to novel intermediates of the method.

[Prior Art] 3,3'-dihydroxyisodocosacarbenyltrimethylbenzene of formula I ((1), 〇_胡罗β素-3,3'-diol) as a feed additive Very important (br〇iler chicken skin pigmentation: Riv. Zootec. Vet. 1974, 15 31- 44; egg yolk pigmentation: Z. Allg. Mikrobiol. (1970), 10 (4), 237-244) ° Various methods for preparing φ,φ_carotene-3,3'-diol by fermentation are illustrated in this document. These methods typically have very low space/time yields. In addition, in order to separate the pure formula; [pigment, which requires very complicated purification operations, makes it difficult to achieve an industrially economical implementation (j. Ind. Microbiol. Biotechnol. 243 15 64-70 (2000); Riv. Zootec .

Vet. 1974, 1, 31-44; Phytochemistry 22, 11, 207-210, 1983). To prepare the pure formula (1), 〇_carotene _3,3, diol, a total chemical synthesis route can be selected. German Patent No. 1593440 illustrates the synthesis of alcohols with carotenoids _3,3,·2 121373.doc 200811095. At the end of this synthesis, according to the reaction diagram below, crocetin dialdehyde 1 and two equivalents of scale salt 2 are olefinated according to the synthetic strategy c1G + C2G + (:1〇 by double Wittig) to obtain Φ of formula I, Φ-carotene _3,3,_diol.

R = tetrahydropyranyl protecting group 1 · Wei Weixi reaction 2. Elimination of protecting group Φ, Φ-carotene-3, 3*-diol according to German Patent Brother 1 5 9 3 4 4 'Example 2, After removing the protecting group from 2 5 8 g (8 7 2 mmol) of the acid of formula 1, only 1.5 g of φ of formula I, φ carotene _3,3'-diol (2.68 mmol) was obtained. Ear = theoretical value of 3 〇 · 7 〇 / 〇). The scale salt of the formula 2 required for this synthesis is prepared from the 2,3,6-trimethyl·4· group of the formula η by the fourth order and the fourth order. According to German Patent No. 1593440, Example 1, 14.6 g (89.02 mmol) of the aldehyde of Formula 11 produced only 64 g (11.133⁄4 mol) of the scale salt of Formula 2. This yield is also unsatisfactory.

KJ -

Tetrahydropyranyl protecting group 12.5% of theoretical value R (Invention content)

121373.doc 200811095 The tabletop-3,3'-diol salaries, + < new head method provides novel intermediates. [Embodiment] This object is achieved by the method for preparing 3,3,·di-diisoisodocesenedimetatriphenylbenzene of the formula 1,

ΟΗ It includes at least one of the following steps: a) making a single ketal of formula II

Wherein the 'group R' is the same or different, preferably the same #, and is a Ci_C8_ alkyl group, or the two groups R1 are commonly double-bonded C2_Ci2_alkylene groups, ie, atoms bonded thereto Forming a cyclic ketal, especially a 5- or 6-membered cyclic ketal; reacting with a metallated alkyne of the formula Ilia or 111b:

Wherein the 'R system can be converted into a group-containing ether, a methacrylate or an acetal protecting group by hydrolysis, and a lanthanum Li, Na, κ, MgC, MgBr, ton or

Mgm, a compound of formula mb may be a mixture of E isomers, z isomers or E/Z isomers, 121373.doc 200811095 to form a C15 building block of formula IVa or IVb,

If appropriate, the C15 structural unit of the formula IVa' or IVb' is obtained by reacting a structural unit of the formula IVa or Ivb2Cl5 with a reducing agent, in particular with a complex of aluminum hydride, to convert the triple bond to a double bond.

b) deprotecting the C15 structural unit of the formula V4Vb by hydrolysis to eliminate the protecting group of the CM structural unit of the formula IVa, m, ..., or

Vb is then introduced by the C15 of the VIb, and the H protecting group is removed by hydrolysis to obtain the formula Via or

Via

Vlb wherein Y is 1- or and 121373.doc 200811095 R2 is an ether, decyl ether or acetal protecting group which can be converted to a hydroxyl group by hydrolysis, c) by reducing a carbonyl group to give a formula Via or VIb The C15 ketone is reacted as a secondary C15 alcohol of the formula Vila or Vllb,

Wherein Y and R2 are as defined in the formula via) in step b), d) reacting a secondary alcohol of the formula Vila or Vllb with a strong organic or inorganic acid and with a diarylphosphonium (aryl) 3, X An anion of an acid hydrazine and an aryl group which is substituted or unsubstituted, and an intermediate C15 phenol which can be isolated by the formula of 111 & or Vlllb

R3 is OH or R2, and R and Y are as defined in step b), wherein the Cl5 scale salt of formula IX or IX' is obtained.

The C15 scale salt of the formula IX can be similar to the C15 scale salt of the formula X IX by the c15 scale salt, e) the C15 of the formula IX is locked, and the partial hydrogenation of the second bond is converted into the formula Ιχ, 7 ·Dimethyl osin-2,4,6-triene 121373.doc •10- 200811095

The compound of formula I is obtained by a double Wittig reaction, and the compounds of the formulas IVb, IVb, Vb, VIb, V11b, Vlllb, XI and IX' may be E isomers, Z is isoforms. A mixture of constructs or E/Z isomers. Preferably, in the process of the invention for the preparation of φ,φ-carotene-3,3,-diol, at least step d) is carried out, and particularly preferably steps d) and e) are carried out, in particular step a ), b), c), d) and e). In step a) of the process of the invention, a monoketal of the formula:

Wherein the 'R1 groups are the same or different', especially (four), and are.丨_. An alkyl group, especially a Ci_C4_alkyl group, such as methyl, ethyl, n-propyl or n-butyl, or the two groups R1 are a double bond 2C2-Cl2-alkylene a radical ', especially a C2_C8_alkylene group, that is, a ring that is attached thereto to form a cyclic ketal, especially a 5- or 6-membered cyclic ketal, for example,

B R4, R5 or R6 are independently hydrogen or Ci_C4_ danyl, such as methyl propyl or n-butyl, especially cyclic ketals. 121373.doc 200811095

Reaction of Me with a metal alkyne of formula III a or 111b

Ma m is preferably a metallated alkyne of the formula Ilia, wherein the R2 is an ether, a methyl hydroxyalkyl ether or an acetal protecting group which can be converted to a hydroxyl group by hydrolysis, in particular

And M1 is Li, Na, K, MgCl, MgBr, Mgl or Mgi/2, especially Li, Na, MgCl or MgBr, excellent Li, the compound of formula 111b can be E isomer, Z is the same a mixture of isomers or E/Z isomers to give C15 structural units of formula IVa or IVb, and preferably IVa,

If appropriate, by means of a structural unit of formula IVa or IVbiCu with a reducing agent (specifically, s and complexes are nitrided), for example, rivastigmine, diisobutylaluminum hydride and bis(2-methoxyethoxyl) The reaction of the sodium sulphate) converts the triple bond to a double bond to form the formula IVa' or IVb, and is preferably iva, the C" structural unit, 121373.doc • 12- 200811095

The monoketal of the formula η used in the step a) can be known in a known manner (zh. 〇rg. Khim. 26, 5, pp. 1087_1091; 199 〇. English translation, 936 94 ,, 1990). 2,3,5_trimercaptobenzoquinone (mimanns

Encyclopedia 〇f industrial Chemistry, Volume A, Volume 485

Page; 1969) Preparation.

Preferably, the cyclic monoketal of formula 114 or 11 is used in step a).

Wherein R4, R5 or R6 are independently hydrogen or Cl_C4_alkyl, especially a single enthalpy of the formula π-a-1 or ΙΙ-b-l

金属Φ-1 The metallated alkyne of the formula Ilia and the formula Illb can be obtained from an alkyne of the known formula ma_a (European Patent No. 63325 8) and 1111)-1) (European Patent No. 5748), 121373.doc -13- 200811095

Wherein R2 is an ether, a methyl hydroxyalkyl ether or an acetal protecting group which can be converted into a hydroxyl group by hydrolysis, preferably

More preferably, in process step a), the starting material is an alkyne of formula IIIa-a. We generally know the acetylation of a carbonyl group in a monoketal of the formula Π-bl with propargyl alcohol (Zh· Org. Khim. 27, 7, pp. 1423-1428, 1991; English translation 1245- Page 1249, 1992; Zh· Org. Khim. 26, 5, pp. 1087-1091, 1990; J. Org. Chem. USSR (English translation) ΕΝ 26, 936-940, 1990) ° For example, unprotected Propargyl 3-methylpent-4-en-1-yn-3-ol

After metallization with 2 equivalents of ethylmagnesium bromide, it was added to the monoketal of the formula ΙΙ-b-1. The yield of the resulting diol of the formula Vila is 68% of theory (J. Org. Chem. USSR, ΕΝ 26, p. 936 et s; 1990). 121373.doc -14· 200811095

Similarly, a formula IIIb-b-OH, a grade of propargyl alcohol, 3-methylpenta-3-di-1-ynyl 5-alcohol

The lllb-b-OH is converted to the diol of the formula ¥111) in a yield of 38% (211.0 Qiao. [111111.27, 7, page 1423 and thereafter; 1991, English translation, page 1245 and later; 1992) .

0H The sterols of the formula Va-a and Vb-b can be obtained from the hydrolysis of the ketal protecting group from Vila and Vllb.

In the process of the invention, the use of a protected propargyl alcohol of formula IIIa-a or IIIb-b (according to process step a)) in the monoketal alkynylation of formula II provides a substantially improved yield. For example, in the addition reaction, the products of the formulae IVa and IVb are obtained in a yield of more than 90%. 121373.doc -15- 200811095 The rut U is also in step a), making the single shrink _ and the heart of the heart

In order to carry out the addition of a monoketal of the formula 藉 by using the alkyne of the formulae 11a-a and IIIb-b with an alkali metal or alkaline earth metal decylamine, hydride, organolithium or format (Grignard) reagent in an inert solvent ( For example, an open chain or cyclic ether or a hydrocarbon) is converted to the corresponding metallated alkyne of formula IIIa or IIIb. For the rapid deprotonation of hydrocarbons, it is preferred that the base is lithium amide or organic lithium, and particularly preferred herein is butyl lithium. The molar ratio of the metallated alkyne of formula IIIa-a or IIIb-b to the monoketal of formula π is typically between 1:1 and 1.5:1, preferably between ι and 3:1. between. Excess alkyne can be separated from IVa or IVb by distillation and recycled to the synthesis. The triple bond in the structural unit of formula IVa or IVbiCw is converted to a double bond by means of a reducing agent to give a structural unit of the formula IVa' or IVb'iC". In principle, the reducing agent can be hydrogenated using the complex for the reduction of propargyl alcohol. Aluminium, especially nitrided by aluminum, diisobutylaluminum hydride and bis(2-decyloxyethoxy)dihydrocarbazide (Helv_Chim·Acta 73, 868, 1990). The reduction is in an inert ring or open The chain ether (diethyl ether, decyl tert-butyl ether, THF) or an open chain or cyclic hydrocarbon such as hexane or toluene is carried out. 121373.doc -16- 200811095 More preferably, the structural unit of the formula IVa-liCb is reduced. The C15 structural unit of formula IVaM is obtained.

In process step b), by hydrolysis, hydrazine acid hydrolysis elimination

Lva, Wb, lva, or lvb, the protecting group of the c15 structural unit is deprotected by the Va or Vb2Cls structural unit,

Vb is then introduced to remove the C15 ketone of formula iVa or IVb by hydrolysis to eliminate the oxime group of π u

/ I. wherein Y is a CH-CH-sfe and R-series can be converted to a base group B1 t ^, a ruthenium group or a carboxylic acid protecting group by hydrolysis, preferably a system

or

121373.doc 0 200811095 In general, the hydrolysis of a protecting group for a ketone functional group in a C15 building block of formula IVa, IVb, IVa' or IVb' in an inert solvent in the presence of water and a catalytically strong acid and protected hydroxy group Both of the functional groups are hydrolyzed to give a C15 structural unit of the deprotected formula Va or Vb. Suitable solvents are inert solvents which are miscible or immiscible with water, such as open chain or cyclic ethers, such as diethyl ether, methyl • tert-butyl ether, THF or dioxane; and hydrocarbons, for example Hexane, heptane, benzene, toluene or diphenyl; and halogenated hydrocarbons such as di-methane, gas, 1,2-dichloroethane, 1,2-dipropane, chlorobenzene, and the like. As the acid, an inorganic acid such as sulfuric acid, hydrochloric acid or hydrobromic acid or phosphoric acid may be used, and a strong organic acid such as methane-, benzene- or toluenesulfonic acid and formic acid, citric acid or trifluoroacetic acid may also be used. Surprisingly skilled in the art, in the case of the C15 structural unit of formula IVa' or IVb', although there is no CC triple bond which has a stabilizing effect on allyl alcohol, there is no rearrangement under acidic reaction conditions. Elimination occurs. Preferably, the C15 building block of formula IVa'-1 deprotects the C15 building block of formula Va'-a. k /

Protection of the free OH group in the C15 building block of formula Va or Vb produces a C15 ketone of the formula Via or VIb. According to the self-document (see, for example, H_ Stalder; Synthesemethoden der organischen Chemie [Synthesis methods in organic chemistry]; the Schweizerische Laboratoriums-Zeitschrift single 121373.doc -18 - 200811095 alone, · first edition, 1978 edition group 0 1978 copyright Knowing the method W into the protecting group 15 structural unit by adding two equivalents of B, preferably the formula Va to protect the Cl5 word alkenyl B - converted to the C15 ketone of the formula Via,

Wherein Y is 1- or .-, and R2 is _0-CH(Me)-〇-CH2CH3. In method step C), the ketone of VIa or vib is converted to the secondary c15 alcohol of the formula Vila or vilb by reduction of the carbonyl group,

Y and R2 are as defined in the formula via in step b). For this step, in principle all hydride reducing agents which reduce the keto group to an alcohol are suitable, for example, the complexes of boron hydride and aluminum hydride, for example sodium borohydride, lithium aluminum hydride, diisobutylene Aluminum hydride and aluminum bis ethoxyethoxy) aluminium hydride. More preferably, the conversion of the C15 ketone of Via to the secondary C15 alcohol of the formula Vila is carried out by reduction,

Vlta

HO 121373.doc •19- 200811095 wherein Y is -CH=CH_ or one C tri C-, and R2 is-0-CH(Me)_0-CH2CH3. Preferably, in the process of the invention for the preparation of Φ, Φ-carotene-3,3'-diol, the C15 ketone of the formula Via or VIb produced in process step b) is used in step c) (un-isolated) And without further treatment) to prepare a secondary C15 alcohol of the formula Vila or Vllb.

In process step d), a secondary Cls alcohol of the formula Vila or Vllb is combined with a strong organic or inorganic acid HX and with a triarylphosphine p (an anion of the aryl acid HX and an aryl substituted or unsubstituted C6) -C14-aryl group) reaction, the intermediate c15 phenol can be separated via the formula Villa or Vlllb,

3 乂 R is OH or R2, and R2 and Y are as defined in formula VIa in step b),

Obtaining Cl5 scale salt of formula IX or IX,

The scaly salt can also be converted to a C 1 5 scale salt of the formula 1: by partial hydrogenation of a triple bond. For the aryl liberation, the secondary C15 alcohol of the formula VIIa4VIIb is subjected to a reaction condition which eliminates the OH protecting group and the female, gans > 121373.doc -20- 200811095 Strong organic or inorganic acid means those whose pKas are less than 3, preferably less than 1. Examples of strong organic or inorganic acids are hydrohalic acids (such as hydrogen acid, hydrogen or hydrogen sulphuric acid), sulphonic acids (such as methanelithic acid, p-toluene or trifluoromethanesulfonic acid), or Trihaloacetic acid (e.g., trifluoroacetic acid or trichloroacetic acid). In the triarylphosphine P(aryl) 3, the aryl groups may be not only substituted but also unsubstituted CrCw-aryl groups, preferably 〇6_〇1()_aryl group The group 'is especially phenyl. The substituent on the aryl group may be, for example, _ and/or K "> 2 ' especially a CrCV alkyl group such as methyl, ethyl, propyl or butyl. Preferably, in process step d), triphenylphosphine is used as the diarylphosphine P(aryl)3. In principle, we know the acid-catalyzed aromatic cyclization of the sterol system (Zh. 〇rg.

Khim, 27, 12, p. 2588 et seq., 1991, English translation, p. 2305 and thereafter; 1992). However, in the literature this is the free tertiary alcohol starting from the ring rather than its protected form, such as the acid. Additionally, the substrate does not contain other allyl alcohol or acetal groups.

Treatment of a secondary C15 alcohol of the formula Vila or Vllb (especially a secondary C15 alcohol of the formula Vila, wherein R2 is -〇-CH(Me)-〇-CH2CH3) under acid-catalyzed acetal elimination conditions, allyl The alcohol functional group is still intact. This result is surprising because those skilled in the art would have expected water to be eliminated or rearranged on the second allyl OH group. 121373.doc •21 · 200811095 It is especially surprising that 'in the presence of strong acid and triphenylphosphine, ie under the conditions of scale salt formation, starting from the secondary Cl5 alcohol of the formula Vila or vilb, can be reached directly in one step The hydrazine salt of formula IX or IX, the reaction is via the separable intermediate of formula VIIIa or V11lb. Preferably, in process step d), in the reaction of a secondary c15 alcohol of the formula villa or Vlllb to a salt of the formula IX or IXAC " sulfonium salt, the strong acid HX uses hydrobromic acid or hydrochloric acid and the triarylphosphine P (aryl) Base 3 uses triphenylphosphine. A preferred reagent for the direct conversion of a secondary C15 alcohol of the formula Vila or Vilb to a Cls scale salt of the formula 使用*ΙΧ, using a triarylphosphine-ruthenium adduct ρ(aryl) 3*ΗΧ, especially triphenyl a phosphinic acid hydrogenate or a triphenylphosphine hydrobromide hydrazine in a preferred embodiment of one of process steps d), a secondary C15 alcohol of the formula Vila,

γ series CH = CH — or — — and R 2 —-0—CH(Me)-0-CH 2 CH 3 is reacted with triphenylphosphine hydrobromide to give a C15 scale salt of formula IX or IX'. Here, the reaction is carried out via C15 phenol of the formula VIIIa-a or VIIIa-b as an intermediate, but it does not need to be isolated as a solid.

IX or 121373.doc -22- IX, 200811095 γ is CH==:CH — or a c 3 c—, and an aryl phenyl group and an X system Br. Partial hydrogenation of the C-C triple bond in the alkyne salt of formula IX' to give the phosphonium salt of formula IX is achieved as described in the literature (European Patent No. 100 839). Preferably, in the step d) of the process of the invention for the preparation of φ,φ-carotene-3,3'-diol, the intermediate of the formula Villa or Vlllb is not isolated, but the second of the formula Vila or Vllb Conversion of a C15 alcohol directly to Formula IX or IX, a C15 scale salt of the formula iVb, IVbf, Vb, VIb, Vllb, Vlllb used or obtained in process steps a), b), c), d) and e) The compounds of XI and IX may be present as a mixture of E isomers, Z isomers or E/Z isomers. In process step e), the sulfonium salt of the formula IXiCw is reacted with 2,7-dimethyloctyl 2,4,6-trienedialdehyde in a double Weiss reaction to give the compound of the formula j. The bismuth salt of the formula IX2C1S and the 2,7-dimethyloctyl-dioxime of the formula X previously not described in the literature can be carried out by a method substantially known from the literature on the process (Reference) "Car〇ten〇ids, Volume 2: Synthesis", Birkhauser Verlag, 1996). The c-C6-alkoxide of the metal or soil-measuring metal for producing the inner-wheel salt is preferably a solution in the corresponding Ci-CV alcohol, and the solvent may be a chlorinated hydrocarbon, for example, dichloromethane. 1,2-dioxaethane, l52-dichloropropane or an open chain or cyclic ether. As the ether solvent, for example, tetrahydrofuran, dioxane or ethylene glycol ether can be used. Hydroxy-containing ethers such as 丨-methoxyprop-2-ol or 2-methoxy-1-enol can also be used. For this reaction, it corresponds to the alkoxide. <6-alcohol (alone or in combination with one of the above solvents) is also suitable. 121373.doc -23- 200811095 Another preferred embodiment produces internal rust salts by means of ethylene oxide as a "latent base" (Chem. Ber. 〇7, p. 2, p. 50 et seq. (1974)), For example, the sulfonate salt of the formula 1X2 Cls is heated in the presence of a dialdehyde of the formula X in an ethylene oxide (preferably hydrazine, 2_butylene oxide) solvent for several hours. The reaction can be carried out in neat ethylene oxide or in a mixture of ethylene oxide and one of the above solvents. The final product of formula I can be isolated by filtering the reaction mixture without additional processing steps. Several examples of the above methods for preparing • diols are exemplified by two specific examples. In the formulas of Figures 1 and 2, Φ, Φ-carotene _3, 3, - 121373.doc -24- 200811095

121373.doc -25- 200811095 Figure 2

IVa^l Vla'-1

However, in Figure 1, the selective hydrogenation of the CC triple bond is carried out until the c15 scale salt of formula IX' is produced, while in Figure 2, the CC triple bond is directly selected after the monoketal alkyneization of formula II. Sexual reduction to CC double bond. The invention further relates to a C15 building block of formula IVa or IVb, 121373.doc -26- 200811095

Wherein the groups R1 and R2 are defined in the manner as set forth above in step a), ie wherein R1 are the same or different, preferably the same oxime, and are a Cl. alkyl group, or two groups. The group is a double-bonded C2-Ci2_alkylene group, that is, a ring that is attached to it to form a cyclic ketal, especially a % or 6-membered cyclic ketal, and the r2 system can be converted by hydrolysis. Is an ether, a carboxyalkyl ether or an acetal protecting group of a hydroxyl group, and the ci5 structural unit of the formula lvb may be a mixture of an E isomer, a Z isomer or an E/z isomer. presence. Especially preferred is the structural unit of the formula IVa2Cls, which is the same as the following formula

The invention is also directed to a C15 building block of formula IVa' or IVb',

Wherein the groups R1 and R2 are defined in the manner as set forth above in step a), ie wherein R1 is the same or different, preferably different, and is C

a Cp alkyl group, or two groups R1 are commonly a double bond, 'Ό心 L2-C12-Extensible 121373.doc -27- 200811095 base group, that is, the atoms connected to it form a ring-shaped shrinkage a ketone, especially a 5- or 6-membered cyclic ketal, and the r2 system can be converted to a hydroxy group 2 ether, a dimethyl ketone ether or an acetal protecting group by hydrolysis, and a Cm structural unit of the formula IVb

It may be a mixture of E isomers, z isomers or E/z isomers. More preferred is the system ΐνα, 2 (^5 structural unit, which is the same as the following formula

Further, the present invention further relates to the structural unit of the formula Va'-aiC^

The invention also relates to a C15 ketone of the formula Via or VIb,

Vlb wherein Y and the group R2 are defined in the manner as set forth above in step b), that is, wherein the Y system is a CH-CH- or CC triple bond, and the R2 is an ether which can be converted to a hydroxyl group by hydrolysis. a formyl ether or acetal protecting group, and of formula VIb. The 1$ ketone may be a mixture of e isomers, Z isomers or e/z isomers. More preferably, the C15 ketone of Via is a Y-system-CH=CH- or C_C triple bond and R2 is a-0-CH(Me)-0-CH2CH3. 121373.doc 200811095 The invention further relates to a secondary C15 alcohol of the formula Vila or Vllb

Wherein, Y and R2 are also as defined in C15_ of the formula Via or VIb, that is, wherein Y is a _CH=CH- or CC triple bond, and R2 is an ether or hydrazine which can be converted into a hydroxyl group by hydrolysis. A decyl ether or acetal protecting group, and the secondary C1S alcohol of formula V11b can be a mixture of E isomers, Z isomers or E/Z isomers. More preferred is a secondary C15 alcohol of the family Vila, wherein R2 is-0-CH(Me)-〇_CH2CH3. The invention also relates to C15 phenol of the formula Villa or Vlllb,

R3 is OH or R2, and R2 and Y are as described in formula VII, and the C15 phenol of formula V11lb may be an E isomer, a Z isomer or an E/Z isomer. mixture. More particularly preferred is C15 phenol of the family Villa, wherein R3 is OH or -O-CH(Me)-o-ch2ch3 〇 The present invention is also directed to c15 scale salts of formula IX or IX',

121373.doc -29- 200811095 wherein aryl and x are defined as described above in step d), ie an anion of the X-based strong organic or inorganic acid HX and the aryl is substituted or unsubstituted The aryl group, and the c15 scale salt of formula IX or IX, may be a mixture of E isomers, Z isomers or E/Z isomers. Preferably, X is CI or Br and the aryl is phenyl. The invention further relates to a process for preparing a C15 scale salt of formula IX,

It includes a secondary C15 alcohol of the formula Vila or Vllb

R2 can be converted to a hydroxyl group by ether, a sulfonium group or a acetylation protecting group, and the C15 alcohol of the formula V11b can be an E isomer, z isomer a mixture of a body or an E/Z isomer, reacting with a strong organic or inorganic acid HX and with a triarylphosphine p(aryl)3, an anion of the lanthanic acid HX and especially a C1 or Br, and an aryl system a substituted or unsubstituted C6-Ci4-aryl group, especially a phenyl group, to give a Cls scale salt, provided that the formula Vila or Vllb is the starting product, wherein 121373.doc -30- 200811095 Y is a two bond 'The C 1 5 scale salt of the two», one of the bonds is converted from a partial hydrogenation to a double bond to reach the formula 1 (^5 scale salt, the formula of the fly 匕5 scale salt can be different The present invention will be exemplified by the following examples, but it is not intended to limit the invention. General details: The preparation and treatment of organic compounds belonging to servants is carried out without air and moisture under protective gas. Example 1 - Synthesis of IVa-liCu structural units

Βυϋ

11 each 1 llla-a-1 In each of the two batches, 1654 g (〇961 mol) of the alkyne of the formula IIIa+l was dissolved in 丨·48 liter of toluene. At (TC), add 335 3⁄4 liters of n-butyl lithium in hexane in 2.5 μl solution (tetra)·_mole

BuU) and the mixture is in the crucible. The armpits disturbed for 3 minutes. Subsequently, a solution of 143.5 g (0.739 mol) of a monoketal of the formula π-b-1 in 3 7 ml of toluene was added dropwise and the mixture was further scrambled with H at GtT. In order to carry out the treatment, 3,073⁄4 liters of ice water was injected. The mixture was again fully discarded for $ minutes and the two batches were combined in a knife funnel. The bottom phase was separated and the top phase was washed twice with 37 Torr of 10% aqueous acetic acid and water. The top phase was dried over sodium sulfate. After filtering off the desiccant, the filtrate was concentrated to 10 mbar at 6 Torr <t on a rotary evaporator. Excess alkyne was separated by vacuum distillation at a film evaporation temperature of 100 C heating temperature and a vacuum of 5-6 mbar. This produces ^^々克 as the thin film evaporator effluent! Va-kCi5 structural unit; this corresponds to a yield of 96% of the theoretical value of 121373.doc -31- 200811095 (based on ΙΜ)_υ. According to gas chromatography analysis, the product had a purity of 97.7%. Synthesis of C15 structural unit of κ-type 2-form Va-a

35 9 g (〇.989 mol) from formula 1 to _1 of Example 1 (^5 structural unit (97.7/. purity) was dissolved in 9903⁄4 liters of tetrahydrofuran. Subsequently, at 2〇c>c to 25 C Next, 178 g (9·89 mol) of water and 23 53 g of a 4% by weight aqueous solution of p-toluenesulfonic acid monohydrate were added in an amount of 49·5 mmol, p-toluenesulfonic acid. Mix the mixture at +5G °C! hour. To carry out the treatment, the batch was diluted with 5 liters of methyl second butyl ether. The organic phase was washed once with 丨 liter of saturated bicarbonate solution and washed twice with 丨 liters of water each time and dried over sodium sulfate. After filtering off the desiccant, the filtrate was concentrated to 20 mbar at 5 (rc) on a rotary evaporator. This gave 236.6 g of 99.1% purity (by gas chromatography) of the formula Va-aiC" Unit (97.3% of theory). For better purification, the product was recrystallized from 500 ml of toluene. This yielded 216 g with 100% purity (by gas chromatography) and ι〇6·5 to l C 7 ° C melting point of the formula Ca-a C15 structural unit. Example 3 - Formula VIa - Ι C15 ketone synthesis

189.6 g (0.77 mol) of the C" structural unit of the formula Va-a of Example 2 121373.doc -32- 200811095 (iv) T_44 liters of f benzene. Add 11 () grams (5 78 mmol) of p-toluene citrate early hydrate and then at 20. . To 25, 208.4 g (2.89 mol) of ethyl ether was added dropwise over 3 minutes. After a further minute drop, another 20 mg (2.89 mmol) of p-toluene acid monohydrate was added and the mixture was stirred for a further 3 hours under the dish. To carry out the treatment', 190 ml of saturated rock anaerobic salt solution was added and the mixture was vigorously vigorous (four) for 5 minutes. The aqueous bottom was separated = the organic top phase was washed once with 19 ml of saturated sodium bicarbonate solution and each person was washed twice with 8 g of water. The organic phase was dried over sodium sulfate. After the desiccant was taken into consideration, the filtrate was concentrated to 5 mbar on a rotary evaporator to give 305. 3 g of the c15 ketone of the formula via_i as a residue, which was further treated as a crude product (without further purification). This crude yield is quantitative. Example 4 - Synthesis of a secondary Ci5 alcohol of the formula Vllaq

In each of the two parallel batches, 152.6 g (0.385 mol, used as received) of the crude C15 ketone of Formula VIa-Ι from Example 3 was dissolved in 154 mL of THF at room temperature. At 〇 ° C, 120 g of a toluene solution having a concentration of 640 ml of this diluted bis(2-methoxyethoxy)dihydrocarbazide was used over 60 minutes. The mixture was stirred at 〇 ° C for an additional hour. Then, a mixture of 77 ml of ethanol and 77 ml of hexane was added dropwise at 〇 ° C, the mixture was further stirred at 〇 C for 15 minutes, and 77 ml of a 15% strength gas oxidized sodium solution was added dropwise at 〇 ° C. The mixture was stirred at 0 Torr for a further 15 minutes. The mixture 121373.doc -33- 200811095 was mixed with 144 ml of water at 0 ° C; the mixture was heated to room temperature and 320 ml of n-hexane was added. The two phase mixture was then transferred to a separatory funnel. The bottom phase was separated and the top phase was washed three times with 77 ml of a semi-concentrated sodium chloride solution each time. The combined bottom phase was extracted once more with toluene. The organic top phases of the two batches were combined, dried over sodium sulfate and the filtrate was concentrated to 5 mbar. This gave 322.9 g of crude crude C15 alcohol of formula VIIa-Ι as a residue; purity by HPLC was 86.2%; this corresponds to 92.2% of theory (based on Cl5 structural unit of formula Va-a). Example 5 - Synthesis of C15 phenol of Villa-1

49.1 g of the crude secondary (~15 alcohol (86.2% purity = 0.108 mol) from the formula 11 to 11 & -1 was dissolved in 500 ml of tetrahydrofuran. 2.63 g (12.5 house mole) 彳 + rubber acid was added. The monohydrate was heated and refluxed for 7 hours. Vj was then cooled to room temperature, diluted with 500 mL of hexane and washed twice with 150 mL of saturated sodium bicarbonate solution, and 1 5 The solution was washed once with a half-concentrated solution of sodium chloride. The combined washed phases were extracted once with 150 ml of n-hexane. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator at +50 ° C. To 1 mbar. This yielded 39.5 g of 88.3% purity (according to HPLC) of crude crude C15 phenol (quantitative yield) of the crude oil of formula vmad. Example 6 - Synthesis of the formula IX'iCn scale salt 121373.doc -34 - 200811095

a) C15 benzoic acid from formula VIIIa-1 1.51 g of C15 phenol from formula VIIIa-1 (88-3% purity = 4.42 mmol) was dissolved in 10 ml of dichloromethane. Under the hydrazine, a solution of 1.56 g (4.55 mmol) of triphenylphosphine hydrobromide in 18 ml of dichloromethane was added dropwise and the mixture was stirred at 〇 ° C for an additional hour. And at room temperature for another hour. The mixture was then concentrated on a rotary evaporator to +5 (TC) to 5 mbar. This gave 2,65 g of crude salt of formula IX as a residue. To crystallize, the residue was dissolved in 20 ml of acetonitrile. This was heated under reflux for 15 minutes, cooled and stirred for an additional 1 hour at 0 ° C. The crystals were filtered, washed with cold cold acetonitrile and dried at + 50 ° C / 20 mbar. Weight: 1.21 g. (: 15 scale salt (49.3% of theory) Melting point: 222.5-223 〇C Purity by HPLC: 98.8% The filtrate was concentrated to 20 mbar at +5 (TC) on a rotary evaporator. This gave 1.24 g of light. a brown viscous oily residue, wherein the content of the sulfonium salt is 39.9 ° / (by HPLC) b) the secondary c15 alcohol from the formula VIIa-Ι will be 39. 2 g from the vila of the example 4 -l of the second-stage cls alcohol (purity 86.2%; = 86.6 millimoles) dissolved in 2 ml of di-methane. After a few hours, 31.2 g of triphenylphosphine hydrobromic acid was added dropwise at 〇 ° C. The salt was stored in 18 ml of dichloromethane. The mixture was stirred for another hour at 〇r and stirred at room temperature of 121373.doc -35-200811095. The salt crystallized, the solvent was distilled off under atmospheric pressure and 500 ml of acetonitrile was added at the same time until the transition temperature was reached + 8 Torr. The obtained suspension was cooled to 〇t, stirred for another hour under 〇t and the product was filtered off. Wash with cold acetonitrile and dry at +5 (rc /2 mbar). Refilled 17.3 g of C15 sulphate of formula IX (36.0% of theory) Purity by HPLC: 96.7%

Melting point: 218.5-219 ° C The filtrate was concentrated to 20 mbar at +50 ° C on a rotary evaporator. The residue was dissolved in 100 ml of acetonitrile. The mixture was stirred at +7 ° C for an additional 5 minutes, cooled to 0 ° C, and stirred at 0 ° C for 1 hour. The second crystals were filtered off, washed with a small amount of cold acetonitrile and dried at <RTIgt;</RTI> Weight: 17.4 g of C15 scale salt of formula IX' (36.2% of theory) Purity by means of HPLC: 99.4% Total yield of C15 sulphate of formula IX': 72.2% of theory. The filtrate of the second crystals was concentrated to 2 mbar at +50 ° C on a rotary evaporator. This gave 18.0 g of a foamy material having a scale salt content of 21.1% (by HPLC) of formula IX. Example 7 - Synthesis of C15 phenol of formula VIIIa-OH

1.96 g of the crude secondary C15 alcohol of formula VIIa-oxime from Example 4 (86.2% purity; = 4.31 mmol) was dissolved in 1 mL of tetrahydrofuran. 0.9 g of 121373.doc -36-200811095 (503⁄4 mol) of water and 240 mg of citric acid monohydrate were added and the mixture was then heated back for 5 hours. It was cooled to room temperature, diluted with 25 ml of methyl t-butyl ether and washed once with 5 ml of saturated sodium hydrogen carbonate solution and twice with 5 ml of water each time. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator to <RTIgt;</RTI> This produced 0.87 grams of a highly viscous yellow oil that crystallized upon standing. The content of C15 phenol of the formula VIIIa-OH (by HPLC): 65.4%; this corresponds to the formula VIIIa_OHi C" The yield of phenol is 574% of theory. For the purpose of characterization, the crude product was dissolved in 4 ml of toluene by heating; it was cooled and allowed to stand at 〇 ° C for 1 hour. The crystals were filtered, washed with a small amount of cold toluene and dried at 50 ° C / 20 mbar. Weight·· 190 mg of C15 phenol of the formula VIIIa-OH Melting point: 132-134 ° C Purity by means of HPLC: 94.8% Example 8 - Synthesis of Cls structural unit of the formula IVa1-1

36. 3 g of the iva^ic" structural unit from Example 1 (97.7% purity) (97.7% purity by GC analysis; = 〇·〇 98 mol) was dissolved in 4 mL of tetrahydrofuran. At 2 ° C, 62 2 g of a 65% strength toluene solution of aluminum bis(2-methoxyethoxy)dihydride diluted with 4 ml of toluene was injected over 1 hour. The mixture was at 0 ° C. Stirring was continued for 2 hours. To carry out the treatment, a mixture of 33 ml of ethanol and 33 ml of n-hexane was first added dropwise (TC373.doc-37-200811095), followed by dropwise addition of 33 ml of 15% sodium hydroxide. Solution. Then add 65 ml of water. Heat the mixture to room temperature. Add 14 ml of n-hexane and remove the aqueous bottom phase. Wash the organic phase three times with half of the concentrated sodium chloride solution. The phases were extracted once with 4 mL of toluene. The combined organic phases were dried over sodium sulfate and concentrated to 5 mbar. Wherein the content of the formula IVa'-liCb structural unit is 88 6% (by gc analysis). This corresponds to the theoretical value of 9 0.7% yield. Example 9 - Synthesis of Cls structural unit of formula Va, -a

36.3 g of the crude Ci5 structural unit of formula IVa, _i from Example 8 (88.6% purity = 88.4 mmol) was dissolved in 100 mL of tetrahydrofuran. 18 g of water and 2.1 g of a 40% strength aqueous solution of p-toluene acid monohydrate (= 5 〇 mmol to -f benzenesulfonic acid) were added and the mixture was stirred at room temperature for an additional hour. For the treatment, 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 liters of water each time, dried over sodium sulfate and concentrated on a rotary evaporator to <RTIgt; This resulted in a residue of 24.8 g of a pale brown solid of the form <"""" This corresponds to a quantitative yield. For the sake of inertness, the crude product of the formula Va'-a was dissolved in 150 ml of toluene 121373.doc -38 - 200811095. The white solution was filtered until it passed through a color filter to indicate that it was transparent and cooled to o. The resulting suspension was stirred at 0 ° C for 1 hour and filtered. The cake was washed with a small amount of cold toluene and dried at 50 °C / 2 0 mbar. Weight: 15.7 g (99.1% purity by GC analysis)

Melting point: 139-140 ° C Example 10 - Synthesis of C15 ketone of Via'-1

14.9 g (60.1 mmol) of the crystalline product of formula Va,_a from Example 9 was suspended in 110 ml of toluene. Iota 73 mg (〇·9 mmol) of p-toluene acid monohydrate was added at room temperature. Subsequently, 21.7 g (3 Torr) of ethyl ether was poured, the temperature of the mixture was raised to +5 (rc and stirred for another 2 hours at +5 Torr). The mixture was cooled to room temperature. Add 15 ml of saturated sodium bicarbonate/cold solution and stir vigorously for another 5 minutes. The aqueous bottom phase is separated and the organic top phase is washed once with 15 ml of saturated sodium bicarbonate solution and also with 6 ml of water each time. It was dried twice with sodium sulfate and concentrated to 1 Torr on a rotary evaporator at <RTI ID=0.0>> - Synthesis of secondary Cl5 alcohols of formula VIIa, -l 121373.doc -39· 200811095

22.3 g of crude C15 ketone (56.9 mmol, used as received) from the form of Example 10, vial, was dissolved in 230 mL of tetrahydrofuran. Next, 17.7 g of a toluene solution of bis(2-methoxyethoxy)dihydrogenated Na 6 6 % > Chen was diluted over 1 hour. The mixture was again scrambled for a few hours and then a mixture of 11 ml of ethanol and U ml of hexane was first injected and 11 k of a 15% strength sodium hydroxide solution was injected after Ik. The mixture was stirred for a further 15 minutes under hydrazine, 22 ml of water and 40 ml of hexane were added and then allowed to warm to room temperature. The aqueous bottom phase was separated and the organic phase was washed three times each time with a half-concentrated sodium chloride solution. The water was combined and extracted once more with mM ml of toluene. The combined organic phases were dried over sodium sulfate and concentrated to 1 mbar at EtOAc. This gave 23.8 g of a crude secondary C15 alcohol of the formula VIIaf-1 as a light brown viscous oil. Example 12 - Synthesis of Ci5 scale salt of formula IX

20.5 g of the crude secondary c15 alcohol (52.0 mmol, used as received) from the vila'-l of Example 11 was dissolved in 1 mL of 2 mL of methane. After i hours, a solution of 1. 6.25 g (46.9 mmol) of triphenylphosphine hydrobromide in 9 liters of monochloropyrene was added dropwise at 0 °C. The mixture was heated to room temperature and then heated under reflux for 2 hours. The solution 121373.doc -40 - 200811095 was then removed on a rotary evaporator to +5 (rc) to 5 mbar. This yielded 28.5 g of a dark solid containing 68.9% of the hydrazine salt of formula IX according to HPLC. This corresponds to a yield of about 66% of the theoretical value of the Cl5 structural unit of the formula Va, -a. The crude product is dissolved in 1 ml of acetone. The precipitate is precipitated by adding 200 ml of ethyl acetate. The solid was separated and dried at +50 ° C / 20 mbar.

Weight: 15.4 g Melting point: 234-235 ° C Example 13 - Formula 3 of 3, 3'-dihydroxyisodocosacarbenium dimercaptobenzene,

136.8 g (0.248 mol) of the formula prepared according to Example 12 was used. 5 scale salts were suspended in 560 ml of ethanol at room temperature. Subsequently, 185 g of 2,7-dimethyloctyl-2,4,6-triazine and 170 ml of U2_butylene oxide were added. The mixture was heated under reflux for 2 hrs. The resulting suspension was cooled to (TC and mixed for 1 hour under the mixture. The furnace was taken up and the filter cake was washed twice with 100 ml of ethanol each time. For better purification, the wet cake was dissolved in 600 ml. In tetrahydrofuran, the suspension was heated under reflux and kept at reflux for 3 minutes. The mixture was filtered hot. Then, 350 ml of solvent was distilled off while 75 ml of acetonitrile was added dropwise. The crystal suspension was shouted for 20 hours. Cool to room temperature, transfer 1 121373.doc -41 - 200811095 hours and filter. Wash the filter cake twice with 50 ml acetonitrile and dry at 50 ° C / 20 mbar. Weight: 38 · 9 g ( 61.5% of the theoretical value)

Melting point: 228-230 ° C HPLC : 98.9% purity EM (CHCI3): 2176 at 465 nm 121373.doc -42-

Claims (1)

200811095 X. Patent application scope: 1. A method for preparing 3,3,-dihydroxyisodocosatrimethylenetriene (3,3'-dihydroxyisoreI1ieratene) of formula I, It comprises at least one of the following steps: a) making a monoketal of formula II: Wherein the groups R1 are the same or different and the t-alkyl group or the two groups R1 are commonly double-bonded C2_c12-alkylene groups, that is, the atoms connected thereto form a ring a ketal; a metallized fast hydrocarbon reaction with the formula Ilia or Illb: Wherein 'R2 is an ether, formazanyl ether or acetal protecting group which can be converted into a hydroxyl group by hydrolysis and the oxime is Li, Na, K, MgCl, MgBr, Mgl or Mg1/2, the formula nib The compound may be a mixture of E isomers, Z isomers or E/z isomers; to form a C15 building block of formula IVa or IVb, 121373.doc 200811095 If appropriate, the C15 building block of formula IVa' or IVb' is then obtained by reacting a C15 building block of formula IVa or IVb with a reducing agent to convert the triple bond to a double bond, IVa, IVb, b) deprotecting the C15 structural unit of formula Va or Vb by hydrolysis to eliminate the protecting group of the C15 structural unit of formula IVa, IVb, IVa1 or IVb', Substituting an OH protecting group which can be eliminated by hydrolysis to obtain a C15 ketone of the formula Via or VIb, Via wherein γ is CH=CH—or C=C—, and R2 is an ether, decyl ether or acetal protecting group which can be converted to a hydroxyl group by hydrolysis, 121373.doc 200811095 C) by reduction a benzyl group reacts a ci5 ketone of formula VIa or vIb to a secondary c15 alcohol of the formula Vila or Vllb, Wherein Y and R2 are as defined in formula VIa in step b), d) reacting a secondary Ci5 alcohol of the formula Vila or VIIb with a strong organic or inorganic acid cerium & with a triarylphosphonium (aryl h, lanthanide) The acid anion and aromatic a substituted or unsubstituted oxime/aryl group through a separable intermediate of formula Villa or Vlllb, Ci5 phenol, Viiib R3 is OH or R2, and R2 and γ are as defined in the formula Via in the step b) to obtain the c15 scale salt of the formula IX or IX'. The Ci5 scale salt of the formula IX* can also be converted to e by partial hydrogenation of the c15 of the formula IX, and the IXiC"scale salt and the formula (2,7-monomethyl osin-2) ,4,6-trienedialdehyde: 121373.doc 200811095 The compound of formula I is obtained by a double Wittig reaction. The compounds of the formulas iVb, IVb, Vb, VIb, Vllb, Vlllb, XI and IX can be E isomers and Z is different. A mixture of bodies or E/Z isomers. 2. The method of claim 1, wherein at least steps d) and e) are implemented. The method of claim 1 or 2, wherein in the method step c), the C15 ketone of the formula Via ia and VIb prepared in the method step b) without isolation and without further treatment is used to prepare the secondary Cl5 alcohol of the formula VIIa4VIIb. . The method of any one of claims 1 to 3, wherein in the method step d) 'to react a secondary C15 alcohol of the formula Vila or Vllb to obtain a C15 scale salt of the formula IX or ΙΧ', a strong acid HX is used Hydrobromic acid or hydrogen acid, and triarylphosphine P (aryl) 3 uses triphenylphosphine. The method of any one of claims 1 to 4, wherein in the method step d), the intermediate of the formula Villa or V11lb is not separated, but the secondary C15 alcohol of the formula Vila or Vllb is directly reacted to obtain the C15 scale of formula IX or IX', a C15 building block of formula IVa or IVb, 121373.doc 200811095 wherein R is the same or different and is a Ci-Cs-alkyl group or a two-bonded alkyl group of the two groups y, which is a ring-bonded atom a ketal, and R2 is an ether, a methacrylate or an acetal protecting group which can be converted into a hydroxyl group by hydrolysis, and the structural unit of the formula IVbiC!5 can be an E isomer, z is the same A mixture of isomers or E/Z isomers. As for the item 6 of the request! 5 structural unit, wherein the formula IVa is the same as the following formula: a formula IVa, or IVb, a C15 structural unit, R1 is the same or different and is a Ci-C8_alkyl group or the two groups R1 are commonly a double-bonded C2-Cl2-extension group, that is, a ring formed by a common atom a ketal, and R2 is an ether, a methyl ketone ether or a carboxylic acid protecting group which can be converted into a hydroxyl group by hydrolysis, and the structural unit of the formula 1Vb' can be an E isomer, z is the same A mixture of constructs or E/Z isomers. 121373.doc 200811095 9. The structural unit of claim 1 of claim 8 wherein the formula IVa is the same as 10·—the c15 structural unit of the formula Va,-a, 11· A C15 ketone of the formula Via or VIb, Wherein Y is a CH-CH- or a CSC-, and the R-series can be converted from a hydrolysis to a mystery group, a methalone or an acetal protecting group, and the C15 ketone of the formula VIb can be A mixture of E isomers, Z isomers or E/Z isomers. 12. The C15 ketone of Via of the formula 11 wherein gamma is -CH-CH- or -CEC-, and R2 is -0-CH(Me)-0-CH2CH3. 121373.doc -6 - 200811095 13· - a secondary c15 alcohol of the formula Vila or Vllb, Wherein the γ system CH == CH""- or ~C=C-, and the R system can be converted into a group-based scale, a mazyl ether or an acetal protecting group by hydrolysis, and the formula The secondary C" alcohol of Vllb can be a mixture of E isomers, z isomers or E/Z isomers. 14. A secondary Ci5 alcohol of the formula Vila according to claim 12, wherein R2 is _〇_CH(Me)_〇-CH2CH3. 15·—C15 phenol of the type Villa or Vlllb, R is the same as OH or R2' and R2 and Y are as defined in formula VIIa of claim 13, and the formula VI1Ibi Cb phenol may be E isomer, z isomer or E/Z a mixture of isomers. 16. The C15 benzene of the Villa of the formula 1 5, wherein the R3 is the same as 〇H or -〇-CH(Me)-〇-CH2CH3. 17·—C15 scale salt of formula IX or IX’, 121373.doc 200811095 p<(aryl) 3x, wherein X is an anion of a strong organic or inorganic acid HX and the aryl is a substituted or unsubstituted C6-C14_aryl group, and the C15 onium salt of the formula IX or IX' It may be a mixture of E isomers, Z isomers or E/Z isomers. 18. A method of preparing a scale salt of formula IX, It comprises a secondary C15 alcohol of the formula Vila or Vllb: Wherein γ is CH=CH—or ~C=C—, and R2 is an ether, a methyl hydroxyalkyl ether or an acetal protecting group which can be converted into a hydroxyl group by hydrolysis, and the secondary C15 alcohol of the formula V11b can be a mixture of E isomers, Z isomers or E/Z isomers; with strong organic or inorganic acids HX and with triarylphosphines P(aryl)3, X series 121373.doc 200811095 The anion of the acid HX and the aryl = substituted or unsubstituted cvc14_aryl group to give a C15 scale salt, provided that the gamma triple bond is used as a starting product, the cls The triple bond of the scale salt can be converted to a C15 scale salt of the formula IX by partial hydrogenation to a C15 scale salt of the formula IX. The C15 scale salt of the formula IX can be an E isomer, a Z isomer or an E/Z. a mixture of isomers. 121373.doc 200811095 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 121,373.doc