Manufacture of alpha, beta, gamma, delta or beta, gamma, delta di-unsaturated ketones carrying a terminal carboxyl group

Abstract

The present invention relates to synthesis of carboxy group terminated di-unsaturated ketones having C=C double bonds at the α,β and γ,δ position or at the β,γ and γ,δ position relative to the carbonyl carbon atom. These ketones can be obtained easily and in few steps from respective alkynols having a terminal carboxyl group. These ketones are important key building block for the synthesis of derivatives of isoprenoids, especially of vitamin E.

Description

[0001] MANUFACTURE OF ALPHA, BETA, GAMMA, DELTA OR BETA, GAMMA, DELTA DI-UNSATURATED KETONES CARRYING A TERMINAL CARBOXYL GROUP Technical Field The present invention relates to di-unsaturated ketones having C=Cdouble bonds at the ^,^ and ^^,^ position or at the ^,^^ and ^,^ position relative tothe carbonyl carbon atom carrying a terminal carboxyl group and particularly to thefield of derivatives of isoprenoids, especially vitamin E.Background of the invention Zhao et al. describe metabolic pathways of tocopherols and tocotrienols,also showing carboxy-terminating tocotrienols in "Analysis of Multiple Metabolitesof Tocopherols and Tocotrienols in Mice and Humans", J. Agr. Food Chem, vol.58, no. 8, 28 April 2010 (2010-04—28), pages 4844-4852. However, no route ofsynthesis for those compounds is provided.In Weichet J., Bláha L., Collect. Czech. Chem. Commun.1966, Vol.31,2424 – 2433 the synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoicacid, which corresponds to isophytol (3,7,11,15-tetramethylhexadec-1-en-3-ol)having a terminal carboxyl group, is disclosed. Said compound is prepared in a very complex reaction sequence starting from 2-methyl-6-oxoheptanoic acid. The described route involves the formation of 2,6-dimethyl-10-oxoundec-6-enoic acid, which is a mono-unsaturated ketone,having a C=C double bond at the ^,^ position relative to the carbonyl carbon atomof the keto group, carrying a terminal carboxyl group. This synthetic pathwayrequires multiple chemical reactions (see also left part of figure 1 and 2) including several chlorination reactions with highly toxic and corrosive hydrogen chloridegas or highly concentrated hydrochloric acid.In the synthesis of isoprenoids, particularly of isophytol, the molecule istypically built up by a sequence of C2 / C3 elongation reactions. One of the knownsynthetic approaches uses the formation of allene ketones for these C2 / C3 elongation reactions. However, for its formation strong acids as catalysts are necessary. US 3,029,287 and G. Saucy et al. in Helv. Chim. Acta 1967, 50(4), 1158-1167 disclose the condensation of a tertiary propargyl alcohol and a ketal or anenol ether to form a beta-allenyl ketone in the presence of strong acids,particularly sulfuric acid or phosphoric acid or p-toluenesulfonic acid. However, the use of strong acid in the preparation of allene ketones isdisadvantageous as these chemicals are particularly hazardous in the handling. These chemicals require specific resistant materials and equipment in the manufacturing process. EP2621879 discloses a different approach for the manufacture ofunsaturated poly-isoprene-ketones by reaction of dehydronerolidol with a vinyl ether. Furthermore, due to the presence of the carboxyl group, it is highly questionable if the person skilled in the art would even have used these reaction steps known from isophytol for the synthesis for 14-hydroxy-2,6,10,14-tetra- methylhexadec-15-enoic acid. Summary of the invention Therefore, the problem to be solved by the present invention is to offer aprocess for preparing intermediates which can be used for the synthesis of 4- hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid which do not use highly corrosive substances and requires significantly less reaction steps than the state-of- the-art process.Surprisingly, it has been found the process according to claim 1 offers a solution to this problem. It is particularly surprising that said process smoothly yields the desiredintermediate product, i.e. the unsaturated ketone of the formula (I), particularly inthe absence of a strong acid. Compared to the state of the art, it has been shown that for the formation of a compound of the formula (I) considerably fewer reaction steps are needed,which is very advantageous in view of time, cost and impurity profile of thecompound of formula (I) and of subsequent reaction products. Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims. Detailed description of the invention In a first aspect, the present invention relates to a process for the manufacture of an unsaturated ketone of the formula (I) by the reaction of a compound of the formula (II) with a compound of the formula (IIIa) or (IIIb) wherein R3represents a methyl or an ethyl group; R4represents H or methyl or an ethyl group; R5represents a linear or branched C1-10-alkyl group, particularly a methyl or an ethyl group; R5'and R5''represent either a linear or branched C1-10-alkyl group, particularly a methyl or an ethyl group; or R5'and R5''form together a linear or branched C1-10-alkylene group, particularly an ethylene or propylene group; and wherein n stands for a value of 1 to 2 and m stands for a value of 0 to 2 with the proviso that the sum of n and m is 1 or 2, and wherein the substructures in formula (I) or (II), represented by s1 and s2,can be in any sequence; R represents a group of the formula (IVa) or (IVb) and any wavy line represents either independently from each other a carbon- carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond (IVb), or represents the corresponding axial R or Senantiomer (IVa) or a mixture thereof,and any dotted line represents a bond by which the substituent of formula (IVa) or (IVb) is bound to the rest of formula (I). For sake of clarity, some terms used in the present document are defined as follows: In the present document, a “Cx-y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e., for example, a C1-3-alkyl group is an alkyl group compri- sing 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CH(CH3)-CH2-CH3is considered as a C4-alkyl group. In the present document, a strong acid is any acid which has a pKa of lessthan 4, particularly of less than 2, preferably less than 1, measured in water atroom temperature. The “pKa” is commonly known as negative decadic logarithm of the acid dissociation constant (pKa = -log10 Ka). In case identical labels for symbols or groups are present in several formulas, in the present document, the definition of said group or symbol made inthe context of one specific formula applies also to other formulas which comprisesthe same said label. The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that identically designated substitu- ents, moieties, or groups can occur simultaneously with a different meaning in the same molecule. In the present document, any dotted line in any formula represents thebond by which a substituent is bound to the rest of a molecule. In the present document, any wavy line in any formula representsindependently from each other a carbon-carbon bond which is either in the Z or inthe E-configuration with respect to an isolated or conjugated C=C double bond. Itis preferred that the configuration is in the E-configuration, i.e. that the (E)-stereoisomer is preferred. If there are several such wavy lines in a specificformula, it is preferred that all double bonds are in the E-configuration. If thecarbon-carbon bond is a cumulated C=C=C double bond, the wavy line in anyformula represents the corresponding axial R or S enantiomer or a mixturethereof. Compound of the formula (I) The compound of formula (I) is a ketone carrying a terminal carboxyl group which has two C=C double bonds. It is preferred that m=0, i.e. that the unsaturated ketone of the formula (I) is an unsaturated ketone of the formula (Ia) In one of the embodiments of the compound of the formulas (I) or (Ia),said double bonds are in the ^,^ and ^,^^positions, relative to carbonyl group of theketo group, and, hence, it is of the formula (Iaa), preferably of the formula (Iaaa) The two C=C double bonds are, in this embodiment, cumulated. Said ketone of the formula (Iaa) or formula (Iaaa) represents, hence, an allene ketone.In another embodiment of the compound of the formulas (I) or (Ia) saiddouble bonds are in the ^,^^and ^,^ positions, relative to carbonyl group of theketo group, and, hence, it corresponds to the formula (Ibb), preferably of theformula (Ibbb), The two C=C double bonds are, in this embodiment, conjugated. Saidketone of the formula (Ibb) and (Ibbb) represents, hence, an ^,^,^,^-unsaturatedketone. In a further embodiment, the process yields a mixture of an allene ketone of the formula (Iaa) and an ^,^,^,^-unsaturated ketone of the formula (Ibb) Preferably a mixture of an allene ketone of the formula (Iaaa) and an ^,^,^,^-unsaturated ketone of the formula (Ibbb), A very preferred allene ketone of the formula (Iaa) is the allene ketone of the formula (I-A) wherein any wavy line either represents independently from each other a carbon-carbon bond which is either in the Z- or in the E-configuration withrespect to the C=C double bond in (Ibb) or (Ibbb), or represents thecorresponding axial R or S enantiomer of (Iaa), (Iaaa) or (I-A) or a mixturethereof. A further very preferred allene ketone of the formula (Iaa) is the alleneketone of the formula (I-AA) or of the formula (I-AAA), preferably of formula (I-AA), wherein any wavy line represents independently from each other a carbon- carbon bond which corresponds to the axial R or S enantiomer of (I-AA) or(I-AAA) or a mixture thereof.A very preferred ^,^,^,^-unsaturated ketone of the formula (Ibb) is the ^,^,^,^-unsaturated ketone of the formula (I-B) wherein any wavy line represents independently from each other a carbon- carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond in (I-B).A very preferred ^,^,^,^-unsaturated ketone of the formula (Ibb) is the^,^,^,^-unsaturated ketone of the formula (I-BB) or (I-BBB), preferably (I-BB), wherein any wavy line represents independently from each other a carbon- carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond. Compound of the formula (II) Of the compound of formula (II), the 3 embodiments of the formula (II-1),(II-2) and (II-2a), particularly (II-1) and (II-2), are preferred embodiments the first being 6-hydroxy-2,6-dimethyloct-7-ynoic acid (II-1) (m=0, n=1); the second being 10-hydroxy-2,6,10-trimethyldodec-11-ynoic acid (II-2) (m=0, n=2) and the third being 10-hydroxy-2,6,10-trimethyldodec-6-en-11-ynoic acid (II-2a) (m=1, n=1) It is preferred that m=0, i.e. that the compound of the formula (II) is an compound of the formula (IIa) The compound of the formula (II-1) can be obtained by ethynylation of 2-methyl-6-oxoheptanoic acid: 2-Methyl-6-oxoheptanoic acid can be obtained by oxidation from 2,6- dimethylcyclohexan-1-one, as shown above, for example by oxidation with potassium permanganate as disclosed on page 1216 in Blahá L. et al., Collect. Czech. Chem. Commun.1965, Vol.30, 1214-1220. The compound of the formula (II-2) can be obtained from 2,6-dimethyl-10-oxoundecanoic acid (V-1a) by ethynylation: 2,6-dimethyl-10-oxoundecanoic acid can be obtained from the compoundof the formula (II-1) by a synthetic pathway as shown in more detail later in thisdocument. The compound of the formula (II-2a) can be obtained from 2,6-dimethyl- 10-oxoundec-6-enoic acid (V-1b) by ethynylation: The ethynylation of 2-methyl-6-oxoheptanoic acid or 2,6-dimethyl-10-oxoundecanoic acid or 2,6-dimethyl-10-oxoundec-6-enoic acid can be performed by reaction of ethyne in the presence of ammonia and an alkali metal hydroxide,such as disclosed for example by WO 2004 / 018400 A1 for the ethynylation of6,10-dimethyl-2-undecanone or by US 4,320,236 or H. Wiederkehr, Chimia, 40(9),1986, 323 – 330.The compound of the formula (II-1) and (II-2) are the most preferred embodiments of the compound of the formula (II). Compound of the formula (IIIa) The compounds of the formula (IIIa) are substances known to the person skilled in the art. In formula (IIIa) R3represents a methyl or an ethyl group and R4represents H or methyl or an ethyl group and R5represents a linear or branched C1-10-alkyl group, particularly a methyl or an ethyl group. Preferably, the group R3represents a methyl group. Preferably, the group R4represents H. Preferably, the group R5represents a methyl group. The compound of the formula (IIIa) is most preferably either isopropenyl methyl ether ("IPM") or isopropenyl ethyl ether ("IPE"), particularly isopropenyl methyl ether ("IPM", 2-methoxyprop-1-ene). Due to the synthesis of compound of the formula (IIIa), very often also mixtures of compounds of the formula (IIIa) are used for the reaction with compound of the formula (II). For example, for butenyl methyl ether, often a mixture of 2-methoxybut-1-ene (E)-2-methoxybut-2-ene and (Z)-2-methoxybut-2-ene, prepared from methanol and methyl ethyl ketone, is used.Compound of the formula (IIIb) The compounds of the formula (IIIb) are substances known to the person skilled in the art. In formula (IIIb) R3represents a methyl or an ethyl group and R4represents H or methyl or an ethyl group. R5'and R5''represent in one embodiment each either a linear or branched C1-10-alkyl group, particularly a methyl or an ethyl group. In another embodiment, R5'and R5''together form a linear or branched C1-10-alkylene group, particularly an ethylene or propylene group. Preferably, the group R3represents a methyl group. Preferably, the group R4represents H. In one preferred embodiment, R5'= R5''and particularly R5'= R5''= methyl or ethyl, more preferably R5'= R5''= CH3. In another preferred embodiment, R5'and R5''form together an ethylene (CH2CH2) or propylene (CH2CH2CH2 or CH(CH3)CH2) group. The compound of the formula (IIIb) is most preferably either 2,2-dimeth-oxypropane or 2,2-diethoxypropane or 2,2-dimethyl-1,3-dioxolane or 2,2,4-tri-methyl-1,3-dioxolane or 2,2-dimethyl-1,3-dioxane. The compound of the formula (IIIb) is most preferably either 2,2-dimeth- oxypropane or 2,2-diethoxypropane, particularly 2,2-dimethoxypropane. The use of the compound of formula (IIIa) is preferred over the compound of the formula (IIIb). In said process for the manufacture of an unsaturated ketone of theformula (I), preferably (Ia), the compound of the formula (II), preferably (IIa), isreacted with a compound of the formula (IIIa) or (IIIb)

[0002] G. Saucy et al. disclose in US 3,029,287 and Helv. Chim. Acta 1967, 50(4), 1158-1167 that the reaction of a tertiary propargyl alcohol and a ketal orenol ether is to be performed in the presence of a strong acid catalyst.Particularly, in a preferred embodiment of the present invention, the reaction of a tertiary propargylic alcohol of formula (II), particularly of (IIa) and the enol ether of formula (IIIa) or the ketal of formula (IIIb) takes place in the absence of any strong acid One might add catalytically active additives to the reaction of thecompounds of formula (II), preferably (IIa), and (IIIa) or (IIIb). However, it has beensurprisingly shown, that said reaction smoothly occurs even in the completeabsence of any added acid.It has been further found that the reaction also occurs smoothly in the absence of any ammonium compounds as catalysts, particularly in the absence of any strong acid or ammonium catalysts. Finally, it has been very surprisingly found, that said reaction smoothlyoccurs even in the complete absence of any added catalysts.The reaction can be carried out without solvent or in the presence of an organic solvent. Even if the reaction is carried out in the absence of an organic solvent, thestarting materials, the compounds of the formula (II) or (IIIa) or (IIIb), may still beprovided in an organic solvent. Thus, there may be an amount of organic solvent up to 10 weight-%, preferably an amount of organic solvent up to 5 weight-%, more preferably an amount of organic solvent up to 3 weight-%, based on the total weight of the reaction mixture. If the reaction is carried out in an organic solvent, aprotic organic solventssuch as aliphatic ketones, such as acetone, or hydrocarbons, such as hexane, arepreferred. It has been found that the above reaction provides the compound of the formula (I) in high conversion, yield and selectivity. It has been found that the reaction is preferably performed when the molarratio of the compound of the formula (II), preferably (IIa), to reaction mixture of thecompound of the formula (IIIa) or (IIIb) is in the range of between 1:15 and 1:2.5,preferably between 1:10 and 1:3.5, more preferably between 1:5 and 1:3.5. The reaction is preferably carried out at a temperature ranging from 70 to170° C. In one embodiment, the temperature is preferably ranging from 110 to160 °C, most preferably at a temperature ranging from 115 to 150 °C. Thistemperature range is particularly suitable for isopropenyl methyl ether as compound of the formula (IIIa). In another embodiment, the temperature is preferably ranging from 75 to 100°C, most preferably at a temperature ranging from 80 to 95°C. This tempera- ture range is particularly suitable for butenyl methyl ether as compound of the formula (IIIa). The reaction is preferably carried out at a pressure ranging from 5 to 20bar (0.5 to 2 MPa), more preferably at a pressure ranging from 6 to 15 bar (0.6 to1.5 MPa). The reaction is in one embodiment preferably carried out at a pressure ranging from 5 to 20 bar (0.5 to 2 MPa), more preferably at a pressure rangingfrom 6 to 15 bar (0.6 to 1.5 MPa). This pressure range is particularly suitable forisopropenyl methyl ether as compound of the formula (IIIa). The reaction is in another embodiment preferably carried out at ambient pressure. This pressure is particularly suitable for butenyl methyl ether as compound of the formula (IIIa). Typically, said reaction yields a mixture of the two isomers of the formula(I), preferably of formula (Ia), i.e. the allene ketone of the formula (Ia), preferably of formula (Iaa), and the ^,^,^,^-unsaturated ketone of the formula (Ib), preferablyof formula (Ibb). Depending on the conditions used for the reaction the ratio of compoundof the formula (Ia) / (Ib), resp. (Iaa) / (Ibb), obtained can vary or even obtained inpure or substantially pure form. In case a mixture is obtained, in one embodiment,the two isomers can be separated. In one of the embodiments, the allene ketone of the formula (Ia), resp. (Iaa) is isomerized to the ^,^,^,^-unsaturated ketone of the formula (Ib), resp. (Ibb). Said isomerization of the allene ketone of the formula (Ia), preferably (Iaa), can be performed by a base or an acid, preferable a base, to yield the ^,^,^,^-unsaturated ketone of the formula (Ib), preferably (Ibb). However, it is preferred that no additional isomerization step is performed before the subsequent reaction step. In a further aspect, the invention relates to a process for the manufacture of a saturated ketone of the formula (V) a) preparing an unsaturated ketone of the formula (I), preferably (Ia), asdisclosed above in great detail; followed directly by b) hydrogenation of the unsaturated ketone of the formula (I), preferably(Ia), from step a); characterized in that between step a) and b) no additional isomerization step by a further base or acid is performed. Surprisingly, it has been observed that the hydrogenation step b) can smoothly performed not only from the unsaturated ketone of the formula (Ib),preferably (Ibb), but also directly from the allene ketone of the formula (Ia),preferably (Iaa) or from a mixture of the allene ketone of the formula (Ia),preferably (Iaa), and the unsaturated ketone of the formula (Ib), preferably (Ibb).Hence, this is very advantageous as any isomerization steps of the alleneketone of the formula (Ia), preferably (Iaa), to the unsaturated ketone of theformula (Ib), preferably (Ibb), would create additional cost and time usage. Hence,said process is very cost beneficial. Typically, the hydrogenation step b) of hydrogenating the compound of theformula (I), preferably (Ia), to the saturated ketone of the formula (V), can beperformed by molecular hydrogen in the presence of a noble metal catalyst. Preferably, the hydrogenation is performed by means of molecular hydrogen in thepresence of a palladium on a solid carrier. Particularly preferred is the noble metalcatalyst selected from the group consisting of palladium on carbon, palladium on silica (SiO2), palladium on TiO2and palladium on aluminum oxide (Al2O3). The molecular hydrogen as described hereinabove can be provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen. The hydrogenation in step b) is preferably carried out under pressure.,particularly under an absolute pressure of between 1 and 21 bar (0.1 to 2.1 MPa),more preferably between 1 and 6 bar (0.1 to 0.6 MPa).The hydrogenation step may be carried out in the absence of an organic solvent. If the hydrogenation step reaction is carried out in an organic solvent, aprotic organic solvents such as hydrocarbons, particularly aromatic hydrocarbons are preferred. In a further aspect, the invention relates to a process for the manufactureof a propargylic alcohol of the formula (II’)a) preparing an unsaturated ketone of the formula (I), preferably (Ia), asprepared as already described in great detail above; followed directly byb) hydrogenation of the unsaturated ketone of the formula (I), preferably(Ia), from step a) to form a saturated ketone of the formula(V); followedbyc) ethynylation of the compound of the formula (V) to yield the compoundof the formula (II’) with the proviso that n= 1 or 2 and R4 = H and R3 = methyl.The compound of the formula (II’) with n=1 (compound of formula (II-2)) is 10-hydroxy-2,6,10-trimethyldodec-11-ynoic acid. The compound of the formula (II’) with n=2 (compound of formula (II-3)) is 14-hydroxy-2,6,10,14-tetramethylhexadec-15-ynoic acid. The conditions for the ethynylation step c) for 2,6,10-trimethyl-14-oxopentadecanoic acid (n=2) (V-2a) or 2,6-dimethyl-10-oxoundecanoic acid (n=1)(V-1a) are the same as already discussed above for the ethynylation of 2 -methyl-6-oxoheptanoic acid. 14-hydroxy-2,6,10,14-tetramethylhexadec-15-ynoic acid, the compound of the formula (II-3), can be hydrogenated selectively to 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid, the compound of the formula (VI), by hydrogenin the presence of a Lindlar catalyst. (II-3) (VI) Suitable methods for this transformation and conditions are disclosed byA. Ofner et al., Helv. Chim. Acta 1959, 42, 2577-2584 or by WO 2020 / 239720 A1or WO 2020 / 239721 A1. Hence, in a further aspect, the invention relates to the use of an allene ketone of the formula (I-A) or (I-AA) or (I-AAA) or an ^,^,^,^-unsaturated ketone ofthe formula (I-B) or (I-BB) or (I-BBB) as described above in great detail as an intermediate for the synthesis of a compound of the formula (VI) 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (VI) can then be reacted with the compound of the formula (VIII) to yield the compound of the formula (VII) R20represents either hydrogen or R'which is a phenol protecting group; and R21 represents, independently from R20, either hydrogen or R' which is aphenol protecting group; and R10and R11and R12represent independently from each other hydrogen or a methyl group. Preferred are the following combinations of R12, R11and R10: R12= R11= R10= CH3or R12= R10= CH3, R11= H or R12= H, R11= R10= CH3or R12= R11= H, R10= CH3. More preferred is that R12= R11= R10= CH3. A phenol protecting group is a group which protects the phenolic group(OH in any of the formulas in this document having R20=H in said formulas) andwhich can be easily removed, i.e. by state-of-the-art methods, resulting to the respective compound with the free phenolic group again. The phenol protecting group R' is introduced by a chemical reaction of the compound of the respective formula having H as R with a protecting agent. The protecting agents leading to the corresponding phenol protecting groups are known to the person skilled in the art, as well as the chemical process and conditions for this reaction. If, for example, the phenol protecting group forms an ester with the rest of the molecule, the suitable protecting agent is for example an acid, an anhydride, or an acyl halide. The phenol protecting group R'is particularly selected from the groups consisting of wherein R30 and R31 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or a C1-15-cycloalkyl or a C6-15-aryl group or a C7-15-aralkyl group; R32 represents a C1-15-alkylene or a C6-15-alkylene group;and wherein either R33 represents a C1-15-alkyl group or an alkyleneoxyalkyl group or apolyoxyalkylene group; R34 represents a C1-15-alkyl group;or R33and R34represent together a C3-7-alkylene group forming a 5 to 7 membered ring; R35 and R36 and R37 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or C6-15-aryl group;and wherein Y1represents either hydrogen or a group of the formula and wherein the single dotted line represents the bond by which said substituent is bound to the rest of a molecule. If R'is equal to R30, the respective compound is an ether, which can be formed by the reaction of the respective protecting agent with the phenolic group (OH). In this case, the protecting agent may be for example an alkylation agentsuch as the respective C1-15-alkyl or fluorinated C1-15-alkyl or C1-15-cycloalkyl orC7-15-aralkyl halide. In one of the preferred embodiments R30is a methyl group. In another preferred embodiment R30is a C6-10-aryl group or a C7-15-aralkyl group, preferably a benzyl group or a substituted benzyl group, particularly preferred a benzyl group.If R' is represented by , the respective compoundis an ester of a carboxylic acid or dicarboxylic acid, which can be formed by the reaction of the respective protecting agent with the phenolic group (OH). If the compound of the respective formula is an ester of a carboxylic acid or dicarboxylic acid, it is preferred that R'is an C1-7-acyl, preferably acetyl, trifluoroacetyl, propionyl or benzoyl group, or a substituted benzoyl group. Esters can be easily deprotected under the influence of an acid or a base. , the respective compound is an acetal, which can be formed by the reaction of the respective protecting agent with the phenolic group (OH). In this case, the protecting agent may be for example, a respective aldehyde, alkyl halide, e.g. MeO(CH2)2OCH2Cl, or an enol ether, e.g.3,4-dihydro- 2H-pyran. In this case, the substituent R'is preferably In some instances, acetals are also called “ethers”, particularly in the cases mentioned above: methoxymethyl ether (MOM-ether), β-methoxyethoxy- methyl ether (MEM-ether) or tetrahydropyranyl ether (THP-ether). Acetals can be easily deprotected under the influence of acids. In another preferred embodiment, the respective compound is an ester of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulphuric acid or sulphurous acid. Depending on the reaction conditions, the esterification is either complete or partial, leaving some residual acid groups of the respective acid non-esterified. It is most preferred that the protecting group R'is a benzoyl group or a C1-4- acyl group, particularly acetyl or trifluoroacetyl group, more particularly acetyl group. The molecules in which R'represents an acyl group, particularly an acetyl group, can be easily prepared from the corresponding unprotected molecule by esterification, and the unprotected phenolic compound can be obtained from the corresponding ester by ester hydrolysis. Most preferred protecting group R'is an acetyl group. The most preferred compound of the formula (VIII) is 2,3,6- trimethylhydroquinone (TMHQ) (VIII-A). Accordingly, the most preferred compoundof the formula (VII) is the compound of the formula (VII-A), or its mono- or di-acetate.It has been found that the condensation reaction of the compound of theformula (VI) and the compound of the formula (VIII) to yield the compound of the formula (VII) can be performed as as disclosed by Weichet J., Bláha L. et al.,Collect. Czech. Chem. Commun.1966, Vol. 31, 2434 – 2443.In a further aspect, the invention relates to the use of an allene ketone ofthe formula (I-A) or (I-AA) or (I-AAA) or an ^,^,^,^-unsaturated ketone of theformula (I-B) or (I-BB) or (I-BBB) as described above in great detail as an intermediate for the synthesis of a compound of the formula (VII) R20represents hydrogen or R'which is a phenol protecting group; and R10and R11and R12represent independently from each other hydrogen or a methyl group. In a further aspect, the invention relates to the process for the manufacture of a compound of the formula (VI) characterized in that it comprises the steps i) preparing an unsaturated ketone of the formula (I), preferably of theformula (Ia), which is prepared as disclosed above in great details (I) Finally, in a further aspect, the invention relates to the compound of the formula (VII) and to its process of manufacture characterized in that in its synthesis a step a) is comprised ofa) preparing an unsaturated ketone of the formula (I), preferably (Ia), whichis prepared according to a process for the manufacture of an unsaturated ketone of the formula (I), preferably (Ia), as disclosed above in great detail. Reaction sequence By the sequences of reactions described above, particularly thecompound of the formula (VII) can be synthesized from 2,6-dimethylcyclohexan-1-one respectively from 6-hydroxy-2,6-dimethyloct-7-ynoic acid in a significantlylower number of steps as compared to a synthesis based on the disclosure ofWeichet J., Bláha L., Collect. Czech. Chem. Commun.1966, Vol. 31, 2424 – 2433.This advantage is particularly due to the inventive process for the manufacture of an unsaturated ketone of the formula (I), respectively (Ia). This is visualized by the reaction sequence shown in figures 1, 2, 3 and 4.In the left part of figure 1 and 2 the multistep process of the state-of-the- art process (marked by REF) is schematically shown using the compound numbering (shown in italics and font Times New Roman) as used in Weichet J.,Bláha L., Collect. Czech. Chem. Commun.1966, Vol. 31, 2424 – 2433.In the right part, the reactions are shown based on the present invention(marked by INV). Figure 1 represents a reaction scheme from of 2-methyl-6-oxoheptanoic acid to 2,6-dimethyl-10-oxoundecanoic acid (V-1a). Figure 2 represents the further reaction sequence, i.e. from 2,6-dimethyl- 10-oxoundecanoic acid (V-1a) to 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a). Figure 3 represents the reaction sequence from 2,6-dimethyl-10-oxoundec-6-enoic acid (V-1b) to 10-hydroxy-2,6,10-trimethyldodec-6-en-11-ynoic acid (II-2a) and the further reaction to 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a). In these three figures, the compound of the formula (I-A) resp. (I-AA) resp.(I-AAA) are displayed. It is evident from the disclosure above that at this step thecompound of the formula (I-B) resp. (I-BB) resp (I-BBB), respectively a mixture ofthe compound of the formula (I-A) and (I-B) resp. a mixture of (I-AA) and (I-BB), resp. a mixture of (I-AAA) and (I-BBB) could be present instead In these formulas, any wavy line either represents independently fromeach other a carbon-carbon bond which is either in the Z- or in the E-configurationwith respect to the C=C double bond ((I-B), (I-BB), (I-BBB)), or represents thecorresponding axial R or S enantiomer ((I-A), (I-AA), (I-AAA)) or a mixture thereof.It is preferred that a mixture of the compound of the formula (I-A) and (I-B)resp. a mixture of (I-AA) and (I-BB) resp. a mixture of (I-AAA) and (I-BBB) ispresent. From figure 1, it is evident that in the left part at least 7 reaction steps are needed whereas on the right part only 2 reaction steps are needed to get from compound of the formula (II-1) to compound of the formula (V-1a). Figure 2 shows the further reaction sequence of the compound of the starts with the compound of the formula (V-1a). Figure 3 shows that in another embodiment, the reaction sequence startswith the compound of the formula (V-1b). The hydrogenation of the compound ofthe formula (I-AAA) can performed in such a way that the compound of the formula (V-2a) is obtained directly. It is evident that in the left part at least 7 reaction steps are needed whereas on the right part only 2 reaction steps are needed to get from compoundof the formula (II-2) to compound of the formula (V-2a), respectively fromcompound of the formula (II-2a) to compound of the formula (V-2a). Figure 4 finally represents the further reaction sequence, i.e. from 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a) to the compound of the formula (VII), (VII-A) As can be seen from the figures 1 to 4, the reaction pathways based onthe present invention leads to a saving of at least 10 reaction steps starting frommethyl-6-oxoheptanoic acid, or the compound of the formula (II), particularly from the compound of the formula (II-1), respectively, to the compound of the formula (VII), particularly of the formula (VII-A)! Examples The present invention is further illustrated by the following experiments. Numbers behind the compounds described below refer to the compounds in the figures.Synthesis of 2-methyl-6-oxoheptanoic acid (1)2,6-Dimethylcyclohexan-1-one (109 ml, 784 mmol) was emulsified in a mixture of water (1140 mL) and acetone (360 mL). The colourless mixture washeated to 50 °C (inner temperature, pre-heated oil bath with 60 °C bath tempera-ture), the oil bath was removed, and potassium permanganate (351 g, 2197 mmol) was added in 9 portions in 30 min intervals, keeping the inner temperature between 51 and 55 °C, upon which it turned purple. It was stirred at 50 °C for 16 h (oil bath). After cooling to room temperature, the dark brown suspension was filteredand the filter cake was washed with water (320 mL) and acetone (110 mL). The acetone was removed under reduced pressure and solid NaCl (350 g) was added to the aqueous solution. This was then washed with ethylacetate (EtOAc), tert.-butyl methyl ether (tBME), and tetrahydrofuran (THF) (250 mL each), THF (500mL) was added, and acidified to pH 1 using conc. aq. HCl (130 mL). The phases were separated and the aqueous phase was extracted one more time with THF (250 mL). The combined organic phases were stirred with solid MgCl2(4 g) for 30 min, then dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The crude product was dissolved in 500 mL of tBME, cooled to 0 °C(water / ice bath), and 2.5 N NaOH (500 mL) was added to bring the pH to 14. The phases were separated and the aqueous phase was washed with tBME (2 x 250 mL), then cooled to 0 °C again and acidified to pH 1 using conc. aq. HCl (112 mL). After extraction with tBME (500, then 2 x 250 mL), the combined organic phases were dried (MgSO4), filtered, and the solvent was removed under reducedpressure to give 98.0 g of a yellow oil (77% purity by q-NMR, 61%), which was further purified to 91% purity (q-NMR) by vacuum distillation. The identity of so theobtained 2-methyl-6-oxoheptanoic acid (1) was verified by the following analyticalcharacterization: Characterisation of 2-methyl-6-oxoheptanoic acid:1H NMR (300 MHz, CDCl3) δ [ppm] = 1.19 (d, J = 6.97 Hz, 3 H), 1.39–1.52 (m, 1H), 1.55–1.74 (m, 3 H), 2.14 (s, 3 H), 2.40–2.53 (m, 3 H).13C NMR (75 MHz, CDCl3) δ [ppm] = 16.8 (CH3), 21.3 (CH2), 29.9 (CH3), 32.8(CH2), 39.2 (CH), 43.4 (CH2), 182.6 (Cquat), 208.7 (Cquat). HRMS (ESI) (C8H13O3+): 157.0871; Calculated.: 157.0870.Synthesis of 6-hydroxy-2,6-dimethyloct-7-ynoic acid (II-1)Before contact with ethyne, all equipment was evacuated and filled with nitrogen (four cycles). In a 1 L autoclave, ammonia (150 g, 8.81 mol) was added to a mixture of KOH (40 g) in water (299 mmol, 42%) and 2-methyl-6-oxohepta- noic acid (1) (20 g, 120 mmol) at 15°C. The reaction was performed by addition ofethyne (9.4 bar (0.94 MPa), 1200 rpm) over one hour. The solvent (ammonia) wasevaporated. The autoclave was opened and the residue was sucked out with water and ethyl acetate. The reaction mixture was acidified to pH 5 with aq. HCl (25%) at 0°C. After phase separation, the organic layer was washed with water (3x 100 mL). The combined aqueous phases were extracted with ethyl acetate (2x 100 mL). The combined ethyl acetate phase was dried (Na2SO4), filtered, and con- centrated under reduced pressure. The crude product was isolated as a viscous brown oil (22.2 g, 93.1% purity (GC-ESTD, calibrated), yield 94%). The identity ofso the obtained 6-hydroxy-2,6-dimethyloct-7-ynoic acid (II-1) was verified by thefollowing analytical characterization: Characterisation of 6-hydroxy-2,6-dimethyloct-7-ynoic acid:1H NMR (300 MHz, CDCl3) δ [ppm] = 1.20 (d, J = 6.97 Hz, 3 H), 1.40–1.79 (m, 9H), 1.40–1.62 (m, 6 H), 2.43–2.56 (m, 2 H), 2.43–2.46 (m, 1 H).13C NMR (75 MHz, CDCl3) δ [ppm] = 16.8 (CH3), 22.2 (CH2), 29.8 (CH), 33.3(CH2), 39.2 (CH3), 43.1 (CH2), 67.9 (CHquat), 71.5 (CH), 87.4 (Cquat), 182.7 (Cquat). HRMS (ESI) (C10H17O3+): 185.1175; Calculated.: 185.1172.Synthesis of 2,6-dimethyl-10-oxoundeca-6,7-dienoic acid (I-A) and 2,6-dimethyl-10-oxoundeca-6,8-dienoic acid (I-B) 6-Hydroxy-2,6-dimethyloct-7-ynoic acid (II-1) (8.22 g, 97.2 w%, 43.4mmol) and 2-methoxyprop-1-ene (IPM) (12.8 g, 17 mL, 98 w%, 173 mmol) were added to a 100 ml stainless steel reactor. The reactor was closed and the solution was heated at 110 °C for 300 min. After cooling to room temperature, the solution was transferred to a round bottomed flask and concentrated under reduced pressure to give the desired product mixture of 2,6-dimethyl-10-oxoundeca-6,7- dienoic acid (I-A) and 2,6-dimethyl-10-oxoundeca-6,8-dienoic acid (I-B) as an orange oil (70% yield of all isomers, GC, ESTD). For comparison the above reaction has been repeated by using sulfuricacid as catalyst in an amount of 1 mol-%, relative to the amount of 6-hydroxy-2,6-dimethyloct-7-ynoic acid (5.46 g, 97.2 w%, 28.8 mmol). A mixture of 2,6-dimethyl-10-oxoundeca-6,7-dienoic acid (I-A) and 2,6-dimethyl-10-oxoundeca-6,8-dienoic acid (I-B) as an orange oil was obtained (70% yield of all isomers, GC, ESTD) and characterized as shown below. From this, it can be observed that the desired product can be obtained inthis reaction in high yields and purity, surprisingly even in the absence of a strongacid. Characterisation:1H NMR (300 MHz, CDCl3) δ [ppm] = 1.14–1.19 (m, 3 H), 1.35–1.73 (m, 4 H),1.84–1.90 (m, 3 H), 2.11–2.34 (m, 5 H), 2.39–2.53 (m, 1 H), 5.94–6.14 (m, 2 H),7.30–7.52 (m, 1 H), 10.87 (s, 1 H).13C NMR (75 MHz, CDCl3) δ [ppm] = 17.0 / 17.1 (CH3), 17.5 (CH3), 24.5 (CH3),25.2 / 25.9 (CH2), 27.56 / 27.60 (CH3), 32.7 / 40.2 (CH2), 33.1 / 33.2 (CH2), 39.28 / 39.32 (CH3), 124.0 / 124.9 (CH), 128.56 / 128.61 (CH), 139.3 / 139.8 (CH), 150.9 / 151.2 (Cquat), 182.5 / 182.7 (Cquat), 199.28 / 199.33 (Cquat). HRMS (EI, after silylation) (C16H28O3Si1-): 296.1794; Calcd.: 296.1808.FT-IR: ν̃ [cm−1] = 734, 889, 971, 1164, 1369, 1463, 1582, 1621, 1664, 1703, 1732,2938.Synthesis of 2,6-dimethyl-10-oxoundecanoic acid (V-1a)In a 1 L steel autoclave, the mixture of 2,6-dimethyl-10-oxoundeca-6,7-dienoic acid (I-A) and 2,6-dimethyl-10-oxoundeca-6,8-dienoic acid (I-B) (56.0 g,250 mmol) was dissolved in EtOAc (450 mL).5% Pd / C (560 mg) was added andthe mixture was purged 3 times with nitrogen (pressurised to 5 bar (0.5 MPa) andreleased) and 3 times with hydrogen (pressurised to 5 bar (0.5 MPa) andreleased). The reaction mixture was heated to 60 °C, pressurised with 5 bar (0.5MPa) H2 and stirred for 3.5 h. After cooling to room temperature, the mixture wasfiltered over a 0.45 µm membrane filter, rinsing with EtOAc, and the solvent wasremoved under reduced pressure. The crude product was purified to yield 2,6-dimethyl-10-oxoundecanoic acid (V-1a) and characterized as shown below.Characterisation:1H NMR (600 MHz, CDCl3) δ [ppm] = 0.84 (d, J = 6.6, 3 H), 1.04–1.13 (m, 2 H),1.22–1.44 (m, 6 H), 1.48–1.69 (m, 3 H), 2.13 (s, 3 H), 2.39 (ddd, J = 7.9, 6.7, 2.8,2 H), 2.41–2.48 (m, 1 H).13C NMR (151 MHz, CDCl3) δ = 16.9 / 17.0 (CH3), 19.55 / 19.57 (CH3), 21.4 / 21.5(CH3), 24.7 (CH2), 30.0 (CH3), 32.59 / 32.61 (CH), 33.85 / 33.90 (CH2), 36.50 / 36.54 (CH2), 36.75 / 36.76 (CH2), 39.50 / 39.54 (CH), 44.19 (CH2), 183.1 (Cquat), 209.70 / 209.71 (Cquat) HRMS (EI, after silylation) (C16H32O3Si1+): 200.2126; Calcd.: 300.2121.FT-IR: ν̃ [cm−1] = 735, 808, 942, 1165, 1235, 1291, 1361, 1377, 1414, 1463, 1703,1737, 2564, 2656, 2865, 2933.Synthesis of 10-hydroxy-2,6,10-trimethyldodec-11-ynoic acid (II-2)Before contact with ethyne, all equipment was evacuated and filled with nitrogen (four cycles). In a 1 L autoclave, ammonia (150 g, 8.81 mol) was added to a mixture of KOH (29.3 g) in water (219 mmol, 42%) and 2,6-dimethyl-10-oxoundecanoic acid (V-1a) (18.8 g, 56.6 mmol) at 15°C. The reaction wasperformed by addition of ethyne (9.4 bar (0.94 MPa), 1200 rpm) over one hour.The solvent (ammonia) was evaporated. The autoclave was opened, and theresidue was sucked out with water and toluene. The reaction mixture was acidifiedto pH 1 with aq. H2SO4 (30%) at 0 °C. After phase separation, the organic layerwas washed with water (3x 100 mL). The combined aqueous phases were extracted with toluene (2x 100 mL). The combined toluene phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was isolated as a viscous brown oil (21.1 g, yield 87%). The identity of so the obtained 10-hydroxy-2,6,10-trimethyldodec-11-ynoicacid (II-2) was verified by the following analytical characterization:Characterisation of 10-hydroxy-2,6,10-trimethyldodec-11-ynoic acid:1H NMR (300 MHz, CDCl3) δ [ppm] = 0.88 (d, J = 6.59 Hz, 3 H), 1.09–1.21 (m, 5H), 1.26–1.55 (m, 12 H), 1.59–1.75 (m, 3 H), 2.39–2.56 (m, 2 H).13C NMR (75 MHz, CDCl3) δ [ppm] = 16.9 (CH / CH3), 19.6 (CH / CH3), 22.0 (CH2),24.5 (CH2), 29.7 (CH / CH3), 32.5 (CH / CH3), 33.8 (CH2), 36.7 (CH2), 36.9 (CH2), 39.3 (CH / CH3), 43.7 (CH2), 68.1 (Cquat), 71.3 (CH), 87.7 (Cquat), 182.7 (Cquat). HRMS (EI) after silylation (C21H41O3Si2+): 397.2578; Calcd.: 397.2594. Synthesis of 2,6,10-trimethyl-14-oxopentadeca-10,11-dienoic acid (I-AA) and 2,6,10-trimethyl-14-oxopentadeca-10,12-dienoic acid (I-BB) 10-hydroxy-2,6,10-trimethyldodec-11-ynoic acid (II-2) (5.10 g, 87.8 w%,18.0 mmol) and 2-methoxyprop-1-ene (5.00 g, 7.0 mL, 98 w%, 70 mmol) were added to a 100 ml stainless steel reactor. The reactor was closed and the solution was heated at 115 °C for 300 min. After cooling to rt, the solution was transferred to a round bottomed flask and concentrated under reduced pressure to give the desired product mixture of 2,6,10-trimethyl-14-oxopentadeca-10,11-dienoic acid (I-AA) and 2,6,10-trimethyl-14-oxopentadeca-10,12-dienoic acid (I-BB) as an orange oil and purified (5.51 g, 39% (GC, ISTD), 41%) and characterised as shown below. For comparison the above reaction has been repeated by using sulfuric acid as catalyst in an amount of 1 mol-%, relative to the amount of 10-hydroxy-2,6,10-trimethyldodec-11-ynoic acid (12.62 g, 89.8 w%, 44.5 mmol). A mixture of 2,6,10-trimethyl-14-oxopentadeca-10,11-dienoic acid (I-AA) and 2,6,10-trimethyl-14-oxopentadeca-10,12-dienoic acid (I-BB) was obtained as an orange oil and purified (17.1 g, 72 w% (GC, ISTD), 92%) and characterised as shown below. From this, it can be observed that the desired product can be obtained in this reaction in high yields and purity, surprisingly even in the absence of a strong acid.Characterisation reflecting the mixture of isomers of the diene (I-AA) and thediastereomers of the allene (I-BB):1H NMR (600 MHz, CDCl3) δ [ppm] = 0.84–0.87 (m, 3 H), 1.07–1.15 (m, 2 H),1.17–1.20 (m, 3 H), 1.24–1.45 (m, 8 H), 1.62–1.70 (m, 1 H), 2.08–2.17 (m, 2 H),2.26–2.30 (m, 3 H), 2.44–2.50 (m, 1 H), 5.98–6.02 (m, 1 H), 6.06–6.10 (m, 1 H),7.39–7.47 (m, 1 H).13C NMR (150 MHz, CDCl3) δ [ppm] = 17.0, 17.0, 17.0, 17.0, 17.0, 17.1, 17.6, 19.6, 19.6, 19.7, 19.7, 19.7, 21.5, 21.5, 24.5, 24.7, 24.7, 24.7, 24.8, 25.2, 25.9, 25.9, 27.6, 27.9, 27.9, 30.0, 32.5, 32.6, 32.6, 32.6, 32.6, 33.3, 33.9, 33.9, 33.9, 34.0, 36.5, 36.6, 36.6, 36.6, 36.7, 36.7, 36.8, 36.8, 36.8, 36.8, 36.8, 36.9, 36.9, 39.4, 39.5, 39.5, 40.8, 44.2, 123.8, 124.5, 128.2, 128.2, 128.4, 139.5, 139.5, 140.0, 151.9, 151.9, 152.3, 152.4, 182.6, 182.6, 182.8, 182.8, 182.9, 199.3, 199.3, 199.3, 209.6, 209.6.Synthesis of 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a)In a 1 L steel autoclave, the previously obtained purified mixture of 2,6,10-trimethyl-14-oxopentadeca-10,11-dienoic acid and 2,6,10-trimethyl-14-oxopentadeca-10,12-dienoic acid (I-BB) (28.5 g) was dissolved in EtOAc (625mL).5.5 g Pd / C was added and the mixture was purged 3 times with nitrogen(pressurised to 5 barg (barg is understood as “bar gauge”, which is the pressurerelative to (or above) the ambient / atmospheric pressure, thus 5 barg correspondto a relative pressure of 0.5 MPa) and released) and 3 times with hydrogen(pressurised to 5 barg and released). The reaction and the mixture was heated to40 °C, pressurised with 5 bar (0.5 MPa) H2 and stirred for 55 mins. After cooling toroom temperature, it was filtered over a 0.45 µm membrane filter, the solvent wasevaporated and the product was purified by column chromatography on silica gel to give purified 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a) in 99% yield. Further purification by column chromatography on silica gel gave the desired product in 92% purity(q-NMR). Characterisation of 2,6,10-trimethyl-14-oxopentadecanoic acid):1H NMR (300 MHz, CDCl3) δ [ppm] = 0.81–0.86 (m, 6H), 1.00–1.12 (m, 4H), 1.15–1.19 (m, 3H), 1.19–1.45 (m, 11H), 1.46–1.71 (m, 3H), 2.37–2.42 (m, 2H), 2.41– 2.49 (m, 1H).13C NMR (75 MHz, CDCl3) δ [ppm] = 17.0 (CH3), 19.7 (CH3), 19.8 (CH3), 21.6(CH2), 24.5 (CH2), 24.7 (CH2), 30.0 (CH3), 32.7 (CH), 32.8 (CH), 34.0 (CH2), 36.6 (CH2), 36.9 (CH2), 37.0 (CH2), 37.4 (CH2), 39.5 (CH), 44.3 (CH2), 183.0 (Cquat), 209.8 (Cquat). HRMS (EI) after silylation (C21H42O3Si+): 370.2897; Calculated: 370.2903 Synthesis of 14-hydroxy-2,6,10 ,14-tetramethylhexadec-15-ynoic acid (II-3) Before any contact with ethyne, all equipment was evacuated and filled with nitrogen (four cycles). In a 1 L autoclave, 150 g ammonia (8807 mmol) were added to a mixture of 18.07 g KOH 42% in water (135 mmol) and 10.81 g 2,6,10- trimethyl-14-oxopentadecanoic acid (V-2a) (33.21 mmol) at 15°C. The reactionwas performed by addition of ethyne (9.4 bar (0.94 MPa), 1200 rpm) over 1 h. Thesolvent (ammonia) was evaporated. The autoclave was opened, and the residue was sucked out with water and MTBE. The reaction mixture was acidified to pH 1 with HCl (25%) at 0°C. After phase separation the organic layer was washed three times with 100 ml water. The combined aqueous phase was extracted two times with 100 mL MTBE. The combined organic phase was dried (Na2SO4), filtered, and concent-rated under reduced pressure to give 14-hydroxy-2,6,10,14-tetramethylhexadec-15-ynoic acid (II-3), (80% yield). Purification by column chromatography on silica gel yielded the product in 97% purity. Characterisation of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-ynoic acid:1H NMR (600 MHz, CDCl3) δ [ppm] = 0.8–0.8 (m, 3 H), 0.8–0.9 (m, 3 H), 1.0–1.7(m, 27 H), 2.4 – 2.5 (m, 2 H).13C NMR (150 MHz, CDCl3) δ [ppm] = 17.0 (CH3), 19.7 (CH3), 19.8 (CH3), 22.2(CH2), 24.4 (CH2), 24.7 (CH2), 29.9 (CH3), 32.7 (CH), 32.8 (CH), 34.0 (CH2), 36.9 (CH2), 37.0 (CH2), 37.3 (CH2), 37.4 (CH2), 39.5 (CH), 43.8 (CH2), 68.2 (CH), 71.4 (Cquat), 87.8 (Cquat), 138.1 (Cquat). HRMS (ESI) (C20H37O3+): 325.2736, Calcd.: 325.2737. Synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (VI) In a 50 mL glass insert for an autoclave, 14-hydroxy-2,6,10,14-tetra- methylhexadec-15-ynoic acid (II-3) (5.0 g) was dissolved in toluene (30 mL). Lindlar catalyst (5% Pd / CaCO3with 3.5% Pb,1.5 g) and 3,6-dithia-1,8-octandiol (50 mg) were added. The insert was placed inside an autoclave and the mixturewas purged 3 times with nitrogen (pressurised to 5 barg and released) and 3 timeswith hydrogen (pressurised to 5 barg and released). The mixture was heated to 80°C, pressurised with 10 bar (1 MPa) H2 and stirred for 3 h. After cooling to roomtemperature, it was filtered over a 0.45 µm membrane filter, rinsing with toluene, and the solvent was removed under reduce pressure. The crude product was purified by two rounds of column chromatography on silica gel to give 1.17 g (87% purity by q-NMR, 3.12 mmol) (VI) of a light-yellow oil. A portion of the product was further purified by prep-HPLC to give a colourless oil (>99% purity by q-NMR). Characterisation of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid:1H NMR (300 MHz, CDCl3) δ [ppm] = 0.85 (d, J = 6.59 Hz, 6 H), 1.01–1.44 (m, 21H), 1.45–1.57 (m, 2 H), 1.61–1.73 (m, 1 H), 2.36–2.58 (m, 1 H), 5.05 (dd,J = 10.83, 1.22 Hz, 1 H), 5.21 (dd, J = 17.42, 1.22 Hz, 1 H), 5.93 (dd, J = 17.33,10.74 Hz, 1 H).13C NMR (75 MHz, CDCl3) δ [ppm] = 17.1 (CH3), 19.9 (2 CH3), 21.4 (CH2), 24.4(CH2), 24.7 (CH2), 27.8 (CH3), 32.6 (CH), 32.7 (CH), 34.0 (CH2), 36.8 (CH2), 37.0 (CH2), 37.3 (CH2), 37.5 (CH2), 39.5 (CH), 42.8 (CH2), 73.7 (Cquat), 111.7 (CH2), 145.3 (CH), 182.4 (Cquat). HRMS (EI, after silylation) (C26H54O3Si+): 470.3631; Calculated: 470.3612. 2-yl)-2,6,10- 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltrideca- noic acid (VII-A) has been synthesized from 14-hydroxy-2,6,10,14-tetramethyl-hexadec-15-enoic acid (I-B) and is 2,3,6-trimethyl hydroquinone (VIII-A) accordingto the procedure disclosed on page 2439 by Weichet J., Bláha L. et al., Collect.Czech. Chem. Commun.1966, Vol. 31, 2434 – 2443.Characterisation of 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-tri- methyltridecanoic acid:1H NMR (300 MHz, CDCl3) δ [ppm] = 0.84 (dd, J=6.4, 1.9, 6H), 1.00–1.15 (m, 4H),1.18 (d, J=7.0, 4H), 1.21–1.69 (m, 20H), 1.72–1.87 (m, 2H), 2.11 (s, 6H), 2.16 (s, 3H), 2.48 (q, J=6.8, 1H), 2.60 (t, J=6.9, 2H).13C NMR (75 MHz, CDCl3) δ [ppm] = 11.4 (CH3), 11.9 (CH3), 12.4 (CH3), 17.0(CH3), 19.7 (CH3), 19.8 (CH3), 20.9 (CH2), 21.2 (CH2), 23.9 (CH3), 24.6 (CH2), 24.8 (CH2), 31.7 (CH3), 32.8 (2 CH), 34.0 (CH2), 37.0 (CH2), 37.45–37.71 (4 CH2),39.5 (CH), 40.0 (CH2), 117.4 (Cquat), 118.7 (Cquat), 121.2 (Cquat), 122.7 (Cquat),144.6 (Cquat), 145.7 (Cquat), 183.4 (Cquat). HRMS (ESI) (C29H48O4+): 460.3527; Calcd.: 460.3547.

Claims

Claims1. A process for the manufacture of an unsaturated ketone of the formula (I)a compound of the formula (II)with a compound of the formula (IIIa) or (IIIb)R3represents a methyl or an ethyl group; R4represents H or methyl or an ethyl group; R5represents a linear or branched C1-10-alkyl group, particularly a methyl or an ethyl group;R5'and R5''represent either a linear or branched C1-10-alkyl group, particularly a methyl or an ethyl group; or R5'and R5''form together a linear or branched C1-10-alkylene group, particularly an ethylene or propylene group; and wherein n stands for a value of 1 to 2 and m stands for a value of 0 to 2 withthe proviso that the sum of n and m is 1 or 2, and wherein the substructures in formula (I) or (II), represented by s1 and s2,can be in any sequence; R represents a group of the formula (IVa) or (IVb)and any wavy line either represents independently from each other a carbon-carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond (IVb), or represents the corresponding axial R or Senantiomer of (IVa) or a mixture thereof,and any dotted line represents a bond by which the substituent of formula (IVa) or (IVb) is bound to the rest of formula (I).

2. The process according to claim 1 characterized in that the compound of theformula (I) is an allene ketone of the formula (Iaa), particularly of the formula(Iaaa),3. The process according to claim 1 characterized in that the compound of theformula (I) is an ^,^,^,^-unsaturated ketone of the formula (Ibb), preferably ofthe formula (Ibbb),4. The process according to claim 1 characterized in that the process yields amixture of an allene ketone of the formula (Iaa) and an ^,^,^,^-unsaturated ketone of the formula (Ibb), preferably of the formula (Iaaa) and (Ibbb),5. The process according to any one of the preceding claims characterized in that the process is performed in the absence of any strong acid catalyst, saidstrong acid having a pKa of less than 4, particularly of less than 2, preferably less than 1, measured in water at room temperature.

6. The process according to any one of the preceding claims 1 to 5, characterized in that the R3stands for a methyl group.

7. The process according to any one of the preceding claims 1 to 5, characterized in that the R4stands for H.

8. The process according to any one of the preceding claims 1 to 7, characteri-zed in that the molar ratio of the compound of the formula (II) to the com- pound of the formula (IIIa) or (IIIb) is in the range of between 1:15 and 1:2.5, preferably between 1:10 and 1:3.5, more preferably between 1:5 and 1:3.

59. A process for the manufacture of a saturated ketone of the formula (V)comprising the steps a) preparing an unsaturated ketone of the formula (I), preferably (Ia), asprepared by any one of the claims 1 to 8; followed directly by b) hydrogenation of the unsaturated ketone of the formula (I) from step a);characterized in that between step a) and b) no additional isomerization step by a further base or acid is performed.

10. An allene ketone of the formula (I-A)wherein any wavy line represents independently from each other the corresponding axial R or S enantiomer or a mixture thereof.

11. An allene ketone of the formula (I-AA) or of the formula (I-AAA),wherein any wavy line represents the corresponding axial R or S enantiomeror a mixture thereof.

12. An ^,^,^,^-unsaturated ketone of the formula (I-B)wherein any wavy line represents independently from each other a carbon- carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond.

13. An ^,^,^,^-unsaturated ketone of the formula (I-BB)wherein any wavy line represents independently from each other a carbon- carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond.

14. The use of an allene ketone according to claim 10 or 11 or an ^,^,^,^-unsaturated ketone according to claim 12 or 13 as an intermediate for thesynthesis of a compound of the formula (VI)15. The use of an allene ketone according to claim 10 or 11 or an ^,^,^,^-unsaturated ketone according to claim 12 or 13 as an intermediate for thesynthesis of a compound of the formula (VII)R20represents hydrogen or R'which is a phenol protecting group; and R10and R11and R12represent independently from each other hydrogen or a methyl group, and wherein the phenol protecting group is selected from the group consisting ofwherein R30 and R31 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or a C1-15-cycloalkyl or a C6-15-aryl group or a C7-15-aralkyl group; R32 represents a C1-15-alkylene or a C6-15-alkylene group;and wherein either R33 represents a C1-15-alkyl group or an alkyleneoxyalkyl group or apolyoxyalkylene group; R34 represents a C1-15-alkyl group;or R33and R34represent together a C3-7-alkylene group forming a 5 to 7 membered ring; R35 and R36 and R37 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or C6-15-aryl group;and wherein Y1represents either hydrogen or a group of the formulaand wherein the single dotted line represents the bond by which said substituent is bound to the rest of a molecule.

16. The process for the manufacture of a compound of the formula (VI)characterized in that it comprises the step of obtaining the unsaturated ketone offormula (I), preferably of the formula (Ia), by preparing it according to any ofthe preceding claims 1 to 8wherein R3represents a methyl or an ethyl group; R represents a group of the formula (IVa) or (IVb)R4represents H or methyl or an ethyl group; n stands for a value of 1 to 2 and m stands for a value of 0 to 2 with the proviso that the sum of n and m is 1 or 2, and wherein the substructures in formula (I) or (Ia) represented by s1 and s2,can be in any sequence; and any wavy line either represents independently from each other a carbon- carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond (IVb), or represents the corresponding axial R or Senantiomer of (IVa) or a mixture thereof,and any dotted line represents a bond by which the substituent of formula (IVa) or (IVb) is bound to the rest of formula (I), preferably (Ia).

17. A process for the manufacture of the compound of formula (VII)characterized in that its synthesis comprises a step of preparing an unsaturated ketone of the formula (I), preferably (Ia), according to any of the preceding claims 1 to 8,R3represents a methyl or an ethyl group; R represents a group of the formula (IVa) or (IVb)R4represents H or methyl or an ethyl group; wherein n stands for a value of 1 to 2 and m stands for a value of 0 to 2 with the proviso that the sum of n and m is 1 or 2, and wherein the substructures in formula (I) or (Ia), represented by s1 ands2, can be in any sequence;and any wavy line either represents independently from each other a carbon- carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond (IVb), or represents the corresponding axial R or Senantiomer of (IVa) or a mixture thereof,and any dotted line represents a bond by which the substituent of formula (IVa) or (IVb) is bound to the rest of formula (I) or (Ia); and R20represents either hydrogen or R'which is a phenol protecting group; andR10and R11and R12represent independently from each other hydrogen or a methyl group, and wherein the phenol protecting group is selected from the group consisting ofwherein R30 and R31 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or a C1-15-cycloalkyl or a C6-15-aryl group or a C7-15-aralkyl group; R32 represents a C1-15-alkylene or a C6-15-alkylene group;and wherein either R33 represents a C1-15-alkyl group or an alkyleneoxyalkyl group or apolyoxyalkylene group; R34 represents a C1-15-alkyl group;or R33and R34represent together a C3-7-alkylene group forming a 5 to 7 membered ring; R35 and R36 and R37 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or C6-15-aryl group;and wherein Y1represents either hydrogen or a group of the formulaand wherein the single dotted line represents the bond by which said substituent is bound to the rest of a molecule.

18. A compound of the formula (VII)characterized in that in its synthesis a step a) is comprised a) preparing an unsaturated ketone of the formula (I), preferably (Ia), whichis prepared according to any of the preceding claims 1 to 8R3represents a methyl or an ethyl group; R represents a group of the formula (IVa) or (IVb)R4represents H or methyl or an ethyl group; wherein n stands for a value of 1 to 2 and m stands for a value of 0 to 2 with the proviso that the sum of n and m is 1 or 2, and wherein the substructures in formula (I) or (Ia), represented by s1 ands2, can be in any sequence;and any wavy line either represents independently from each other a carbon-carbon bond which is either in the Z- or in the E-configuration with respect tothe C=C double bond, or represents the corresponding axial R or Senantiomer of (IVa) or a mixture thereof,and any dotted line represents a bond by which the substituent of formula(IVa) or (IVb) is bound to the rest of formula (I) or (Ia);andR20 represents either hydrogen or R' which is a phenol protecting group; andR10and R11and R12represent independently from each other hydrogen or a methyl group, and wherein the phenol protecting group is selected from the group consisting ofwherein R30 and R31 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or a C1-15-cycloalkyl or a C6-15-aryl group or a C7-15-aralkyl group;R32 represents a C1-15-alkylene or a C6-15-alkylene group;and wherein either R33 represents a C1-15-alkyl group or an alkyleneoxyalkyl group or apolyoxyalkylene group; R34 represents a C1-15-alkyl group;or R33and R34represent together a C3-7-alkylene group forming a 5 to 7 membered ring;R35 and R36 and R37 represent independently from each other a C1-15-alkyl ora fluorinated C1-15-alkyl or C6-15-aryl group;and wherein Y1represents either hydrogen or a group of the formulaand wherein the single dotted line represents the bond by which said substituent is bound to the rest of a molecule.

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