WO2025125574A1

WO2025125574A1 - Manufacture of allylic alcohols carrying a terminal carboxyl group via ethynylation and lindlar hydrogenation

Info

Publication number: WO2025125574A1
Application number: PCT/EP2024/086231
Authority: WO
Inventors: Fabrice Aquino; Werner Bonrath; Alissa GOETZINGER; Stefan HAESS; Hajo Lehmann; Jonathan Alan Medlock; Francesco Pace; Domenico SORIANO; René Tobias STEMMLER
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2023-12-14
Filing date: 2024-12-13
Publication date: 2025-06-19
Anticipated expiration: 2026-06-14

Abstract

The present invention relates to synthesis of specific allylic alcohols having terminal carboxyl groups based on steps of ethynylation and hydrogenation in the presence of a Lindlar catalyst. These allylic alcohols are particularly useful to offer pathways to syntheses of isophytol or tocopherols having a terminal carboxyl group by a very small number of reactions steps.

Description

MANUFACTURE OF ALLYLIC ALCOHOLS CARRYING A TERMINAL CARBOXYL GROUP VIA ETHYNYLATION AND LINDLAR HYDROGENATION

Technical Field

The present invention relates to the field of formation of allylic alcohols, particularly useful for the synthesis of to isophytol or tocopherols having a terminal carboxyl group and, hence, particularly to the field of derivatives of isoprenoids, especially vitamin E.

Background of the invention

In Weichet J., Blaha L., Collect. Czech. Chem. Commun.1966, Vol. 31 , 2424 - 2433 the synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid, which corresponds to isophytol (3,7,11 ,15-tetramethylhexadec-1 -en-3-ol) having a terminal carboxyl group, is disclosed.

Up to now, 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 y,5 position relative to the carbonyl carbon atom of the keto group, carrying a terminal carboxyl group. This synthetic pathway requires multiple chemical reactions (see also left part of figure 4) including several chlorination reactions by highly toxic and corrosive hydrogen chloride gas or highly concentrated hydrochloric acid.

In the synthesis of isophytol, the molecule is typically built up by a sequence of C2/C3 extension reactions. One of the known synthetic approaches uses tertiary vinyl carbinols or ketals/acetals. G. Saucy et al. disclose in Helv. Chim. Acta 1967, 50, 2091-2095 and Helv. Chim. Acta 1967, 50, 2095-2100 that phosphoric acid or sulfuric acid or p-toluene sulfonic acid can be used as catalyst for the reaction between tertiary vinyl carbinols and isopropenyl ethers. DE 196 49 564 discloses that diverse acidic organophosphorous compounds act as catalysts. WO 2010/046199 A2 discloses inorganic ammonium (NH4⁺) salts as potential catalysts. However, inorganic ammonium salts have typically a disadvantageous solubility, and it has been shown that the inorganic ammonium salts show lower yields and selectivities particularly when used at concentrations of less than 1 mol- %.

However, 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-tetramethylhexa- dec-15-enoic acid.

Weichet J., Blaha L., Collect. Czech. Chem. Commun.1966, Vol. 31 , 2424 - 2433 discloses, furthermore, ethynylation of a saturated ketones as well as Lindlar hydrogenations of alkynes to alkenes. However, ethynylation of unsaturated ketones or alkynes comprising C=C double bonds has been not disclosed. Weichet J., Blaha L. et al., Collect. Czech. Chem. Commun.1966, Vol. 31 , 2434 - 2443 discloses the formation of alpha-tocopheryl acid (= 13-(6-hydroxy-2,5,7,8- tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid) from 10-hydroxy-

2.6.10-trimethyldodeca-6, 11 -dienoic acid.

Summary of the invention

The reaction pathway to prepare carboxyl-term inated allylic alcohols involved in the synthesis of 13-(6-hydroxy-2, 5,7, 8-tetramethylchroman-2-yl)-2, 6,10- trimethyltridecanoic acid (Vll-A), or its intermediates, particularly of 14-hydroxy- 2,6, 10,14-tetramethylhexadec-15-enoic acid (l-B) or 2,6,10-trimethyl-14-oxopenta- decanoic acid (Vl-A), is rather complex and involves a very large number of reaction steps. This high number of reaction step is very disadvantageous in view of time, cost, labor and yield.

Therefore, any process which allows a reduction of the number of steps is highly appreciated.

It has been surprisingly found that the process of claim 1 allows a significant reduction of reaction steps. It has been found that, when starting from 3-methyloctane-2, 7-dione (ll-O) the compounds 2,6,10-trimethyl-14-oxopentadeca-

6.10-dienoic acid (IV-A) can be prepared in only 6 steps, 2,6,10-trimethyl-14-oxo- pentadecanoic acid (Vl-A) in 7 steps, 14-hydroxy-2,6,10,14-tetramethylhexadec-

15-enoic acid (l-B) in 9 steps or 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-

2.6.10-trimethyltridecanoic acid (Vll-A) in 10 steps, respectively, which leads to a significant reduction in time and costs and to a product with an advantageous impurity profile.

Furthermore, it has been particularly surprisingly found that the chain extension involving the compounds of the formula (Va) or (Vb) can be performed in the absence of any strong acids, which contributes to a further reduction in costs as the handling of highly corrosive substances in the synthesis can be avoided. It has been also found that said reaction can be performed in the absence of any ammonium catalysts and shows high yields and selectivities.

These findings lead to a process which is highly advantageous due to reduction of steps and cost in the production.

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 allylic alcohol of the formula (I)

by the steps a) ethynylation of an unsaturated ketone of the formula (II)

to yield a propargylic alcohol of the formula (III)

followed by b) hydrogenation of the propargylic alcohol of the formula (III) formed in step a) using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to yield the compound of the formula (I); wherein n stands for a value of 0 to 3 and m stands for a value of 1 to 3 with the proviso that the sum of n and m is 1 to 3, and where the substructures in formula (I), (II) or (III), represented by s1 and s2, can be in any sequence; and 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 to the C=C double bond.

For the sake of clarity, some terms used in the present document are defined as follows:

In the present document, a “C_x-y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e. , for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CH(CH3)-CH2-CH3 is considered as a C4-alkyl group.

In the present document, a strong acid is any acid which has a pk_a of less than 4, particularly of less than 2, preferably of less than 1 , measured in water at room temperature. The “pKa” is commonly known as negative decadic logarithm of the acid dissociation constant (pKa = -log K_a). 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 in the context of one specific formula applies also to other formulas which comprises the same said label.

The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that identically designated substituents, 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 the bond by which a substituent is bound to the rest of a molecule.

In the present document, any wavy line in any formula represents independently from each other a carbon-carbon bond which is either in the Z or in the E-configuration with respect to the C=C double bond, or mixtures thereof. If there are several such wavy lines in a specific formula, it is preferred that all double bonds are in the E-configuration.

In a first step (step a)), the unsaturated ketone of the formula (II) carrying a terminal carboxyl group is ethynylated.

The unsaturated ketone of the formula (II) comprises at least one carboncarbon double bond. The substructures represented by s1 and s2 in all the respective formulas of this documents, particularly in formula (II), as well as in the of formulas (I, I’, II’, III, III’, IV, IV’ or VI’) as described later on in more detail, can be in any sequence. However, it is preferred that at least one of the substructure elements s2, is directly bonded to the carbonyl, or to the C(CH3)(C=CH)OH, or to the C(CH3)(C=CH)OH group, respectively. In other words, the compound of the formula (II) is preferably a y,6-unsaturated ketone.

It is very surprising that such an unsaturated ketone carrying a terminal carboxyl group of the formula (II) can be ethynylated with high selectivity, and without, or at least with a very significantly reduced amount of, any undesired side products. The ethynylation can be performed by reaction with ethyne in the presence of ammonia and an alkali metal hydroxide, such as disclosed for example by WO 2004/018400 A1 for the ethynylation of 6,10-dimethyl-2-undeca- none or by US 4,320,236 or Chimia, 40(9), 1986, 323 - 330. The unsaturated compound of the formula (II) can be prepared as shown later in this document in more detail.

It is particularly preferred that the ethynylation in step a) is performed in the absence of any organic solvent.

The ethynylation of an unsaturated ketone of the formula (II) in step a) yields a propargylic alcohol of the formula (III).

Said propargylic alcohol of the formula (III) is then hydrogenated in step b) by using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to yield the compound of the formula (I).

It is known that Lindlar catalysts are generally suitable to be used to selectively hydrogenate OC triple bonds to C=C double bonds in propargylic alcohols. Lindlar catalysts, as well as the conditions for this hydrogenation, are known to the person skilled in the art, for example from Lindlar, Helv. Chim. Acta 1952, 35(2), 446-450 or from A. Ofner et al., Helv. Chim. Acta 1959, 42, 2577- 2584.

Preferred Lindlar catalysts are palladium on calcium carbonate doped with lead. Such Lindlar catalysts are for example commercially available from Sigma- Aldrich, Evonik, Johnson-Matthey or Hindustan Platinum.

It is particularly preferred that the amount of palladium in the Lindlar catalyst is preferably in the range of from 1 to 10 weight-%, more preferably in the range of from 3 to 8 weight-%, most preferably in the range of 4 to 6 weight-%, based on the total weight of the Lindlar catalyst. It is further preferred that the amount of lead (Pb) in the Lindlar catalyst is preferably in the range of from 0.5 to 7 weight-%, more preferably in the range of from 1 to 6 weight-%, most preferably in the range of 2 to 5 weight-%, based on the total weight of the Lindlar catalyst.

Said Lindlar catalyst is typically used in an amount of between 0.01 and 50 weight-%, preferably of between 0.1 and 5 weight-%, relative to the propargylic alcohol of the formula (III) in the hydrogenation of step b).

It is particularly surprising that the Lindlar catalysts can be used also for the selective hydrogenation of the specific propargylic alcohol of the formula (III) to the allylic alcohol (I) without reducing the terminal carboxyl group to a hydroxyl group in step b).

Preferably both m and n stand for a value of 1 . Therefore, in a preferred embodiment the compound of the formula (II) is the unsaturated compound of the formula (ll-A) and, accordingly, the compound of the formula (III) is the propargylic alcohol of the formula (lll-A) and the allylic alcohol of the formula (I) is the allylic alcohol of the formula (l-A)

Therefore, the current invention relates also to the allylic alcohol of the formula (l-A) and a propargylic alcohol of the formula (lll-A). It has been found that a compound of the formula (I) can be reacted further with a compound of the formula (V) or (Vb)

in the absence of any strong acid or ammonium catalyst; wherein R³ represents a methyl or an ethyl group;

R⁴ represents H or methyl or an ethyl group;

R⁵ represents a linear or branched Ci -1 o-alkyl group, particularly a methyl or an ethyl group;

R⁵' and R⁵" represent either a linear or branched Ci -1 o-alkyl group, particularly a methyl or an ethyl group; or R⁵' and R⁵" form together a linear or branched Ci-w-alkylene group, particularly an ethylene or propylene group;

Therefore, in another aspect, the invention relates also to a process for the manufacture of the unsaturated ketone of the formula (IV’), particularly of formula (IV), by reacting in step c) an allylic alcohol of the formula (I’), particularly of the formula (I), with a compound of the formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst.

wherein n stands for a value of 0 to 3, and m’ stands for 0 or m, wherein m stands for a value of 1 to 3, with the proviso that that the sum of n and m’ or n and m is 1 to 3 and where the substructures in formula (I’) or (IV’), particularly (I) or (IV), represented by s1 and s2, can be in any sequence; and

R³ represents a methyl or an ethyl group;

R⁴ represents H or methyl or an ethyl group;

R⁵' and R⁵" represent either a linear or branched Ci -1 o-alkyl group, particularly a methyl or an ethyl group; or R⁵' and R⁵" form together a linear or branched Ci-w-alkylene group, particularly an ethylene or propylene group; and any wavy line represents independently from each other a carboncarbon bond which is either in the Z- or in the E-configuration with respect to the C=C double bond.

Compound of the formula (Va)

The compounds of the formula (Va) are substances known to the person skilled in the art.

In formula (V) R³ represents a methyl or an ethyl group and R⁴ represents H or methyl or an ethyl group and R⁵ represents a linear or branched Ci -1 o-alkyl group, particularly a methyl or an ethyl group.

Preferably, the group R³ represents a methyl group.

Preferably, the group R⁴ represents H.

Preferably, the group R⁵ represents a methyl group.

The compound of the formula (Va) is most preferably either isopropenyl methyl ether ("IPM") or isopropenyl ethyl ether ("IPE'), particularly isopropenyl methyl ether ("IPM").

Due to the synthesis of compound of the formula (Va), very often also mixtures of compounds of the formula (Va) are used for the reaction with compound of the formula (I) or (I’). For example, for butenyl methyl ether, often a mixture of 2-methoxybut-1-ene and (E)-2-methoxybut-2-ene and (Z)-2-methoxy- but-2-ene being prepared from methanol and methyl ethyl ketone, is used.

Compound of the formula (Vb)

The compounds of the formula (Vb) are substances known to the person skilled in the art.

In formula (Vb) R³ represents a methyl or an ethyl group and R⁴ represents H or methyl or an ethyl group. R⁵' and R⁵" represent in one embodiment each either a linear or branched CM o-alkyl group, particularly a methyl or an ethyl group. In another embodiment, R⁵' and R⁵" together form a linear or branched Ci-w-alkylene group, particularly an ethylene or propylene group.

Preferably, the group R³ represents a methyl group.

Preferably, the group R⁴ represents 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 (Vb) 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 (Vb) is most preferably either 2, 2-dimeth- oxypropane or 2,2-diethoxypropane, particularly 2,2-dimethoxypropane.

The use of the compound of formula (Va) is preferred over the compound of the formula (Vb).

In said step c) the allylic alcohol of the formula (I’), respectively (I), is reacted with a compound of the formula (Va) or (Vb)

G. Saucy et al. disclose in Helv. Chim. Acta 1967, 50, 2091-2095 and Helv. Chim. Acta 1967, 50, 2095-2100 that phosphoric acid or sulfuric acid or p- toluene sulfonic acid can be used as catalyst for the reaction between tertiary vinyl carbinols and isopropenyl ethers. Therefore, G. Saucy et al. discloses that this reaction is to be performed in the presence of a strong acid catalyst.

Surprisingly, it has been found that said reaction of step c) smoothly occurs also in the complete absence of any added acid.

Furthermore, it has been surprisingly 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 even more surprisingly found, that said reaction of step c) smoothly occurs even in the complete absence of any added catalysts. The reaction of step c) can be carried out without solvent or in the presence of an organic solvent. Preferably the reaction is carried out without solvent.

Even if the reaction of step c) is carried out in the absence of an organic solvent, the starting materials, the compounds of the formula (I’) or (I) or (Va) or (Vb), may still be provided 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, polar aprotic organic solvents such as aliphatic ketones, such as acetone, or hydrocarbons, such as hexane, are preferred.

It has been found that the above reaction step c) provides the compound of the formula (IV’) or (IV) in high conversion, yield and selectivity.

It has been found that the reaction in step c) is preferably performed when the molar ratio of the compound of the formula (I’), respectively (I), to reaction mixture of the compound of the formula (Va) or (Vb) is ranging from 1 :15 to 1 :1 , preferably between 1 :12 and 1 :4, more preferably between 1 :10 and 1 :5.

The reaction is preferably carried out at a temperature ranging from 50 to 170°C. In one embodiment, the temperature is preferably ranging from 70 to 150°C, most preferably at a temperature ranging from 80 to 120°C. This temperature range is particularly suitable for isopropenyl methyl ether as compound of the formula (Va).

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 temperature range is particularly suitable for butenyl methyl ether as compound of the formula (Va).

The reaction is preferably carried out at a pressure ranging from 5 to 20 bar (0.5 to 2 MPa), more preferably at a pressure ranging from 6 to 15 bar (0.6 to 1.5 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 ranging from 6 to 15 bar (0.6 to 1 .5 MPa). This pressure range is particularly suitable for isopropenyl methyl ether as compound of the formula (Va). 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 (Va).

In a preferred embodiment of the formula (IV’), m’ represents a value of m, i.e. m’ = 1 - 3, particularly m’ = 1 .

In a preferred embodiment the compound of the formula (I’) is the compound of the formula (I) which is prepared by a process for the manufacture of an allylic alcohol of the formula (I) as shown above in great detail. In one embodiment, the unsaturated ketone of the formula (IV’), is prepared by a process comprising the subsequent steps

to yield a propargylic alcohol of the formula (III’)

followed by b) hydrogenation of the propargylic alcohol of the formula (III’) formed in step a) using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to yield the compound of the formula (I’); c) reacting the allylic alcohol of the formula (I’)

with a compound of the formula (Va) or (Vb)

in the absence of any strong acid or ammonium catalyst; wherein n stands for a value of 0 to 3, and m’ stands for 0 or m, wherein m stands for a value of 1 to 3, with the proviso that that the sum of n and m’ is 1 to 3 and where the substructures in formula (I’) or (II’) or (III’) or (IV’), represented by s1 and s2, can be in any sequence; and

R³ represents a methyl or an ethyl group;

R⁴ represents H or methyl or an ethyl group;

R⁵' and R⁵" represent either a linear or branched Ci -1 o-alkyl group, particularly a methyl or an ethyl group; or R⁵ and R⁵ form together a linear or branched Ci-w-alkylene group, particularly an ethylene or propylene group; and any wavy line represents independently from each other a carboncarbon bond which is either in the Z- or in the E-configuration with respect to the C=C double bond.

In a very preferred embodiment, the compound of the formula (I’), respectively (I), is an allylic alcohol of the formula ( l-A, )

Hence, in a very preferred embodiment the unsaturated ketone of the formula (IV’) is the unsaturated ketone of the formula (IV-A))

Therefore, the unsaturated ketone of the formula (IV-A) represents another aspect of the present invention.

In figure 1 the different reactions are shown in an overview:

In the first part (see box marked by “f’) the process for the manufacture of an allylic alcohol the formula (I) by ethynylation of an unsaturated ketone of the formula (II) (step a) followed by hydrogenation using a Lindlar catalyst (step b) is shown.

In the second part (see box marked by “If’) the process for the manufacture of the unsaturated ketone of the formula (IV’) or (IV) by reacting an allylic alcohol of the formula (I’) or (I) with a compound of the formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst (step c) is shown.

In the third part ((see box marked by “Ilf’), finally the combination of the first part and second part is shown. Here, the unsaturated ketone of the formula (IV’), particularly of the formula (IV) is manufactured by first ethynylating a ketone of the formula (II’), particularly of the formula (II), (step a) followed by hydrogenation using a Lindlar catalyst (step b) and by reacting the allylic alcohol of the formula (I’) or (I) with a compound of the formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst (step c).

The unsaturated ketone of the formula (IV’) as described hereinabove, particularly the unsaturated ketone of the formula (IV-A), can be hydrogenated to yield a saturated ketone of the formula (VI’), particularly of the formula (Vl-A).

Hence, in a further aspect, the invention relates to a process for the manufacture of the saturated ketone of the formula (VI’), particularly the saturated ketone of the formula (Vl-A),

by the reaction step d) d) hydrogenation of the unsaturated ketone of the formula (IV’), particularly of the unsaturated ketone of the formula (IV-A), in the presence of molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a transition metal catalyst

wherein the transition metal is a transition metal of the groups 7, 8, 9 or 10, particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, more preferably Pd; and n stands for a value of 0 to 3, and m’ stands for 0 or m, wherein m stands for a value of 1 to 3, with the proviso that that the sum of n and m’ is 1 to 3 and where the substructures in formula (IV’) or (VI’), particularly (IV-A) or (VI- A), represented by s1 and s2, can be in any sequence; and 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 to the C=C double bond; characterized in that the compound of the formula (IV’), particularly (IV-A), is prepared by a process for the manufacture of the ketone of the formula (IV’) or (IV-A), as already discussed above in great detail.

The hydrogenation in step d) is performed in the presence of molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a transition metal catalyst, wherein the transition metal is a transition metal of the groups 7, 8, 9 or 10, particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, more preferably Pd.

The hydrogenation can also be carried out in the presence of a reductant or hydrogen donor or a transfer hydrogenation agent, in place of molecular hydrogen. Suitable hydrogen donors or transfer hydrogenation agents are particularly formic acid, formate salts, hydrazine and alcohols such as 2-propanol.

By this hydrogenation all carbon-carbon double bonds present in the molecule of the formula (IV’) are hydrogenated.

Particularly suitable transition metal catalysts are Pd or Pt catalysts. Preferably said transition metal catalysts are transition metal(s) which are supported, i.e. attached to or deposited on a carrier.

Such hydrogenation catalysts are principally known to the person skilled in the art. Platinum and palladium and iridium which are both particularly preferred are noble metals. Therefore, particularly preferred catalysts are supported palladium or platinum catalysts. The carrier is a solid material.

Preferably said carrier is carbon or an inorganic carrier. Preferred inorganic carriers are oxides or carbonates. Preferred oxides are oxides of silicon, aluminum or titanium or cerium or sulfur. Particularly preferred are silicon dioxide, alumina and titanium dioxide and ceria and sulfates.

Silicon dioxide can be used as pyrogenic silica or precipitated or ground silica as carrier. Preferably silicon dioxide used as carrier is pyrogenic or precipitated silica. Most preferred silicon dioxide is a silicon dioxide which is essential pure SiCh. In other words, it is preferred that the silicon dioxide carrier consists of more than 95 %, more preferably more than 98 %, even more preferred more than 99 %, by weight of SiCh.

Calcium carbonate is one of the preferred carbonates. The preferred calcium carbonate is precipitated calcium carbonate.

It is possible that the carrier as used is a mixed oxide.

More preferred hydrogenation catalysts are palladium on carbon, palladium on silica, palladium on alumina and palladium on calcium carbonate.

The amount of palladium in the hydrogenation catalyst is preferably in the range of from 0.5 to 20 weight-%, more preferably in the range of from 2 to 5 weight-%, most preferably in the range of approximately 5 weight-%, based on the total weight of the hydrogenation catalyst.

Another particularly suitable transition metal catalyst is a Ni catalyst such as a nickel alloy catalyst (also known as Raney nickel (Ra-Ni) or sponge nickel, Urushibara nickel, or a supported nickel catalyst such as nickel on silica-alumina.

In a more preferred embodiment, the saturated ketone of the formula (VI’), is prepared by a process comprising the subsequent steps

to yield a propargylic alcohol of the formula (III’)

with a compound of the formula (Va) or (Vb)

R³ represents a methyl or an ethyl group;

R⁴ represents H or methyl or an ethyl group;

R⁵' and R⁵" represent either a linear or branched Ci -1 o-alkyl group, particularly a methyl or an ethyl group; or R⁵' and R⁵" form together a linear or branched Ci-w-alkylene group, particularly an ethylene or propylene group; and any wavy line represents independently from each other a carboncarbon bond which is either in the Z- or in the E-configuration with respect to the C=C double bond; to obtain the compound of formula (IV’), and optionally repeating steps a) to c) followed by d) hydrogenation of the unsaturated ketone of the formula (IV’), particularly of the unsaturated ketone of the formula (IV-A), in the presence of molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a transition metal catalyst

wherein the transition metal is a transition metal of the groups 7, 8, 9 or 10, particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, more preferably Pd; and n stands for a value of 0 to 3, and m’ stands for 0 or m, wherein m stands for a value of 1 to 3, with the proviso that that the sum of n and m’ is 1 to 3 and where the substructures in formula (IV’) or (VI’), particularly (IV-A) or (VI- A), represented by s1 and s2, can be in any sequence; and 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 to the C=C double bond.

The saturated ketone of the formula (VI’), particularly the saturated ketone of the formula (Vl-A), can be ethynylated to form the corresponding propargylic alcohol using the ethynylating step a) as described above in detail.

This is shown in an overview in figure 3.

Therefore, particularly the propargylic alcohol of ketone of the formula (III- B) can be prepared from the ketone of the formula (Vl-A)

Submitting the compound of the formula (lll-B) to hydrogenation using a Lindlar catalyst as described above for step b) yields an allylic alcohol of the formula (l-B)

Hence, a further aspect of the present invention relates to a process for the manufacture of the allylic alcohol of the formula (l-B) comprising the steps

by the steps a) ethynylation of the saturated ketone of the formula (Vl-A)

to yield a propargylic alcohol of the formula ( 11 l-B)

followed by b) hydrogenation of the propargylic alcohol of the formula ( 11 l-B) formed in step a) using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen, donor or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to yield the allylic alcohol of the formula (l-B); characterized in that the saturated ketone of the formula (Vl-A) is prepared according to a process as described above.

The allylic alcohols of the formula (I-0) or (l-A) or ( l-A’ ) or (l-B), preferably (I-0) or (l-A) or (l-B), can be reacted with the compound of the formula (VIII) to yield in a step e) the compound of the formula (Vll-a), or (Vll-b) or (Vll-c) or (VII),

Preferred allylic alcohols for this reaction are (1-0) or (l-A) or (l-B), most preferably (l-B).

Allylic alcohol of the formula (l-A’) might be obtained in the following manner:

Compound of formula (ll-A) is submitted to a hydrogenation step d) as described above to yield the saturated ketone of the formula (ll-A’).

The so obtained saturated ketone of the formula (ll-A’) is then ethynylated in step a) to yield the propargylic alcohol of the formula ( 11 l-A’) The so obtained propargylic alcohol of the formula (I I l-A’) is hydrogenated in step b) using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to yield the allylic alcohol of the formula

The compound of the formula (VIII) is defined as follows:

R¹⁰ and R¹¹ and R¹² represent independently from each other hydrogen or a methyl group; and

R²¹ represents hydrogen or R' which is a phenol protecting group.

Preferred are the following combinations of R¹², R¹¹ and R¹⁰:

R¹² = RH = R¹⁰ = CH₃ or

R12 _{= R}10 _{= C}|_|_{3 R}11 ₌ |_| or

R12 = H, R¹¹ = R¹⁰ = CH₃ or

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 and the protecting group 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 with the rest of the molecule an ester, 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 Ci -1 s-alkyl or a fluorinated Ci -1 s-alkyl or a Ci-15-cycloalkyl or a Ce-is-aryl group or a C7-15- aralkyl group;

R³² represents a Ci-15-alkylene or a Ce-is-alkylene group; and wherein either

R³³ represents a Ci-15-alkyl group or an alkyleneoxyalkyl group or a polyoxyalkylene group;

R³⁴ represents hydrogen or a Ci-15-alkyl group; or

R³³ and R³⁴ represent together a Cs-7-alkylene group forming a 5 to 7 membered ring;

R³⁵ and R³⁶ and R³⁷ represent independently from each other a Ci -1 s-alkyl or a fluorinated Ci-15-alkyl or Ce-is-aryl group; and wherein Y¹ represents 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 agent such as the respective Ci-15-alkyl or fluorinated Ci-15-alkyl or Ci-15-cycloalkyl or C7- 15-aralkyl halide, particularly iodide.

In one of the preferred embodiments R³⁰ is a methyl group.

In another preferred embodiment R³⁰ is a Ce- -aryl group or a C?-i5-aralkyl group, preferably a benzyl group or a substituted benzyl group, particularly preferred a benzyl group.

If R¹ is represented by

, the respective compound is 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 Ci-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)2OCH2CI, or an enol ether, e.g. 3,4-dihydro- 2/-/-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), [3-m ethoxyethoxymethyl 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-trimethylhydro- quinone (TMHQ) (Vlll-A).

(Vlll-A)

Accordingly, the most preferred reaction products thereof are the compounds of the formula (Vll-aa), (Vll-bb), (Vll-cc) and (Vlll-A) or their mono- or diacetates )

Step e), also labeled as step ii) later on in the present document, can be performed as as disclosed by Weichet J., Blaha L. et al., Collect. Czech. Chem. Commun.1966, Vol. 31 , 2434 - 2443.

Hence, a further aspect of the present invention relates to a process for the manufacture of the compound of the formula (VII) comprising the steps i) preparing an allylic alcohol of the formula (l-B)

according to a process for the manufacture of an allylic alcohol of the formula (l-B) as described above; ii) reacting the compound of the formula (l-B) with the compound of the formula (VIII) to yield a compound of the formula (VII)

R²⁰ represents hydrogen or R' which is a phenol protecting group; and R¹⁰ and R¹¹ and R¹² represent independently from each other hydrogen or a methyl group; and

R²¹ represents hydrogen or R' which is a phenol protecting group.

It has been shown that the present invention is particularly useful for the synthesis of the allylic alcohol of the formula (l-B) and/or the compound of the formula (VII) which is very advantageous as it can be performed easily and with significantly less steps than a process based on the prior art. Particularly advantageous is that the reaction sequence avoids any steps which would require the handling of highly toxic and corrosive chemicals, particularly hydrogen chloride gas or highly concentrated hydrochloric acid.

Figures 2 and 3 show schematically a particularly preferred sequence of reaction from 3-methyloctane-2, 7-dione (11-0) to 2,6,10-trimethyl-14-oxopenta- deca-6,10-dienoic acid (IV-A) or 14-hydroxy-2,6,10,14-tetramethylhexadec-15- enoic acid (l-B) or carboxy group-term inated tocopherol or its derivatives (VII), respectively.

The reaction in figure 2 starts with 3-methyloctane-2, 7-dione (I l-O) as starting material. It is ethynylated under the conditions of step a) to yield 6- hydroxy-2,6-dimethyloct-7-ynoic acid (lll-O), which is subsequently hydrogenated under conditions of step b) using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, having more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to 6- hydroxy-2,6-dimethyloct-7-enoic acid (I-0).

6-Hydroxy-2,6-dimethyloct-7-enoic acid (I-0), as prepared in this manner, is then reacted in the in the absence of any strong acid or ammonium catalyst with the compound of the formula (Va) or (Vb), particularly with isopropenyl methyl ether ("IPM") to yield 2,6-dimethyl-10-oxoundec-6-enoic acid (ll-A) (see box marked by II’). These first 3 reaction steps (a,b,c,) are highlighted in figure 2 by the box marked by ///’.

Subsequently, 2,6-dimethyl-10-oxoundec-6-enoic acid (ll-A) is again ethynylated under the conditions of step a) to yield

10-Hydroxy-2,6,10-trimethyldodec-6-en-11-ynoic acid (lll-A), which is subsequently hydrogenated under the conditions of step b) using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to 10-hydroxy-2, 6, 10-trimethyldodeca-6, 11 -dienoic acid (l-A). These 2 reaction steps are highlighted by the box marked by I”.

10-Hydroxy-2, 6, 10-trimethyldodeca-6, 11 -dienoic acid (l-A), prepared in this manner, is reacted in the in the absence of any strong acid or ammonium catalyst with the compound of the formula (Va) or (Vb), particularly with isopropenyl methyl ether ("IPM”) to yield 2,6,10-trimethyl-14-oxopentadeca-6,10- dienoic acid (IV-A) (see box marked by II”). These last 3 reaction steps (a),b),c)) are highlighted in figure 2 by the box marked by III”.

In other words, with two subsequent reaction sequences of steps a),b) and c), 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A) can be prepared in 6 steps only from 3-methyloctane-2, 7-dione (ll-O).

Subsequently 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A), as prepared in this manner, is hydrogenated in step d), as shown in figure 3, to 2,6, 10-trimethyl-14-oxopentadecanoic acid (Vl-A), followed by ethynylation under the conditions of step a) to yield 14-hydroxy-2,6,10,14-tetramethylhexadec-15- ynoic acid (lll-B). 14-Hydroxy-2,6,10,14-tetramethylhexadec-15-ynoic acid (lll-B) is subsequently hydrogenated in conditions of step b) using molecular hydrogen, e.g. provided as a gas comprising hydrogen, the gas preferably having a content of more than 99.9%, more than 99.99% hydrogen, or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (l-B).

In other words, 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (l-B) can be obtained in 9 steps only from 3-methyloctane-2, 7-dione (ll-O).

Finally, 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (l-B) is then further reacted in step e) (=ii)) with the compound of the formula (VIII), particularly with 2,3,6-trimethylhydroquinone (TMHQ) (Vlll-A), to the carboxy group terminated tocopherol or its derivatives of the formula (VII), respectively, particularly to 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6, 10- trimethyltridecanoic acid (Vll-A).

In other words, the carboxy group terminated tocopherol or its derivatives of the formula (VII), particularly 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)- 2,6,10-trimethyltridecanoic acid (Vll-A), can be obtained in 10 steps only from 3- methyloctane-2, 7-dione (ll-O).

The described process in this document is very advantageous over a process which is based on the state-of-the-art document. For illustration purposes the present inventive syntheses are compared with those of Weichet J., Blaha L., Collect. Czech. Chem. Commun.1966, Vol. 31 , 2424 - 2433 in figure 4.

In the left part of figure 4 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 roman) as used in the cited prior art.

In the right part, the reactions are shown based on the present invention (marked by INV).

As one can easily derive from figure 4, 2,6,10-trimethyl-14-oxopenta- decanoic acid (Vl-A) (XII) can be obtained from the starting product 3-methyl- octane-2, 7-dione (ll-O) (II) to in only 8 steps by a reaction pathway based on the invention, whereas the at least 16 steps are needed in the reaction pathways according to the prior art. Accordingly, also for the synthesis of alpha-tocopheryl acid (= compound of the formula (Vll-A)), at least 8 steps can be saved by the reaction pathway based on the invention as compared with the state-of-the-art procedure, i.e. Weichet J., Blaha L., Collect. Czech. Chem. Commun.1966, Vol. 31 , 2424 - 2433 and Weichet J., Blaha L. et al., Collect. Czech. Chem. Commun.1966, Vol. 31 , 2434 - 2443.

Examples

The present invention is further illustrated by the following experiments. Synthesis of 2-methyl-6-oxoheptanoic acid (ll-O)

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 was heated to 50 °C (inner temperature, pre-heated oil bath with 60 °C bath temperature), 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 filtered and the filter cake was washed with water (320 mL) and acetone (110 mL). The acetone was removed under reduced pressure and solid NaCI (350 g) was added to the aqueous solution. This was then washed with ethylacetate (EtOAc), tert.- butyl methyl ether (fBME), and tetrahydrofuran (THF) (250 mL each), THF (500 mL) was added, and acidified to pH 1 using cone. aq. HCI (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 (MgSCU), filtered, and the solvent was removed under reduced pressure.

The crude product was dissolved in 500 mL of fBME, 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 fBME (2 x 250 mL), then cooled to 0 °C again and acidified to pH 1 using cone. aq. HCI (112 mL). After extraction with fBME (500, then 2 x 250 mL), the combined organic phases were dried (MgSCU), filtered, and the solvent was removed under reduced pressure 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 the obtained 2-methyl-6-oxoheptanoic acid (ll-O) was verified by the following analytical characterization:

Characterisation of 2-methyl-6-oxoheptanoic acid: ¹ H NMR (300 MHz, CDCI₃) 6 [ppm] = 1 .19 (d, J = 6.97 Hz, 3 H), 1 .39-1 .52 (m, 1 H), 1.55-1.74 (m, 3 H), 2.14 (s, 3 H), 2.40-2.53 (m, 3 H).

¹³C NMR (75 MHz, CDCI3) 6 [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) (C₈HI₃O3⁺): 157.0871 ; Calculated: 157.0870.

Synthesis of 6-hydroxy-2,6-dimethyloct-7-ynoic acid (III-0)

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 (ll-O) (20 g, 120 mmol) at 15°C. The reaction was performed 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 the residue was sucked out with water and ethyl acetate. The reaction mixture was acidified to pH 5 with aq. HCI (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 concentrated 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 of so the obtained 6-hydroxy-2,6-dimethyloct-7-ynoic acid (III-0) was verified by the following analytical characterization:

Characterisation of 6-hydroxy-2,6-dimethyloct-7-ynoic acid: ¹ H NMR (300 MHz, CDCI3) 6 [ppm] = 1 .20 (d, J = 6.97 Hz, 3 H), 1 .40-1 .79 (m, 9 H), 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, CDCI₃) 6 [ppm] = 16.8 (CH₃), 22.2 (CH₂), 29.8 (CH), 33.3 (CH₂), 39.2 (CH₃), 43.1 (CH₂), 67.9 (CH_quat), 71.5 (CH), 87.4 (C_quat), 182.7 (C_quat).

HRMS (ESI) (CIOHI₇0₃ ⁺): 185.1175; Calculated: 185.1172.

Synthesis of 6-hydroxy-2,6-dimethyloct-7-enoic acid (l-O)

In a 150 mL steel autoclave, 6-hydroxy-2,6-dimethyloct-7-ynoic acid (lll-O) (30.3 g) was dissolved in ethyl acetate (60 g). Lindlar catalyst (5% Pd/CaCO₃ with 3.5% Pb,1.0 g) and 3,6-Dithia-1 ,8-octandiol (200 mg) were added. The autoclave was purged 3 times with nitrogen (pressurised to 5 barg (barg is understood as “bar gauge”, which is the pressure relative to (or above) the ambient/atmospheric pressure, thus 5 barg correspond to a relative pressure of 0.5 MPa) and released) and 3 times with hydrogen (pressurised to 5 barg and released). The reaction mixture was heated to 25 °C, pressurised with 5 bar (0.5 MPa) H₂ and stirred for approximately 10 h. After cooling the reaction mixture was filtered and the solvent was removed under reduced pressure to yield a crude product 6-hydroxy-2,6- dimethyloct-7-enoic acid (30.4 g) (I-0), which was purified by distillation and characterized as followed.

Characterisation of 6-hydroxy-2,6-dimethyloct-7-enoic acid:

¹H NMR (300 MHz, CDCI₃) 5 [ppm] = 1.16 (d, J=7.0, 3H), 1.27 (s, 3H), 1.31-1.57 (m, 5H), 1.57-1.77 (m, 1 H), 2.38-2.51 (m, 1 H), 5.04 (dd, J=10.8, 1.2, 1 H), 5.19 (dd, J=17.4, 1.2, 1 H), 5.89 (dd, J=17.3, 10.7, 1 H), 6.40 (s, 1 H)

¹³C NMR (75 MHz, CDCI₃) 5 [ppm] = 17.0 (CH₃), 21 .6 (CH₂), 27.8 (CH₃), 33.9 (CH₂), 39.4 (CH), 42.1 (CH₂), 73.5 (C_quat), 112.0 (CH₂), 145.0 (CH), 182.7 (C_quat).

FT-IR v (cm^-1) = 735, 918, 995, 1150, 1208, 1281 , 1413, 1464, 1703, 2940, 2973.

HRMS (ESI) (CIOHI₇0₃-): 185.1185; Calculated: 185.1183.

Synthesis of 2,6-dimethyl-10-oxoundec-6-enoic acid (ll-A) 6-Hydroxy-2,6-dimethyloct-7-enoic acid (I-0) (6.86 g, 92.1 w%, 33.9 mmol) and 2-methoxyprop-1 -ene (9.98 g, 13 mL, 98 w%, 136 mmol) were added to a 60 ml stainless steel reactor. The reactor was closed and the solution was heated at 90 °C for 13 h. After cooling to room temperature, the solution was transferred to a round bottomed flask and concentrated under reduced pressure to give the desired product E/Z mixture of 2,6-dimethyl-10-oxoundec-6-enoic acid (ll-A) as an orange oil (7.75 g, 64% combined yield of isomers by GC with internal standard).

The crude product was purified by column chromatography on silica gel.

Characterisation of 2,6-dimethyl-10-oxoundec-6-enoic acid (mixture of (E)- and (Z)- i somers):

¹H N MR (300 MHz, CDCh) 6 [ppm] = 1.12-1.22 (m, 3H), 1.29-1.53 (m, 3H), 1.53- 1.73 (m, 4H), 1.90-2.08 (m, 2H), 2.13 (s, 3H), 2.17-2.32 (m, 2H), 2.36-2.55 (m, 3H), 5.12-4.99 (m, 1 H).

¹³C NMR (75 MHz, CDCI3) 6 [ppm] = 15.9 (CH₃), 16.97/16.99 (CH₃), 22.4/22.5 (CH₂), 23.4/30.1 (CH₃), 25.4/25.5 (CH₂), 31.6/39.4 (CH₂), 33.1/33.4 (CH₂), 39.3/39.4 (CH), 43.9/44.0 (CH₂), 123.0/123.7 (CH), 136.1/136.3 (Cquat), 182.9/183.0 (Cquat), 209.09/209.15 (Cquat).

HRMS (ESI) (C₂iH₄o0₃Si₂-): 225.1501 ; Calculated: 225.1496.

Synthesis of 10-hydroxy-2,6,10-trimethyldodec-6-en-11-ynoic acid (I ll-A)

All equipment which was in contact with ethyne subsequently, 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-oxoundec-6-enoic acid (ll-A) (18.8 g, 56.6 mmol) at 15°C. The reaction was performed by addition of ethyne (9.4 bara (0.94 MPa absolute pressure, which includes ambient/atmospheric pressure), 1200 rpm) for one hour. For work-up, the solvent (ammonia) was evaporated. The autoclave was opened, and the residue was sucked out with water and toluene. The reaction mixture was acidified to pH 1 with aq. H2SO4(30%) at 0 °C. After phase separation, the organic layer was 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 10-hydroxy-2,6,10-trimethyldodec-6-en-11 -ynoic acid was isolated as a viscous brown oil (21.1 g, 59.6 % purity (GC-ESTD), 87%).

Characterisation of 10-hydroxy-2,6, 10-trimethyldodec-6-en-11-ynoic acid:

¹H N MR (300 MHz, CDCI₃) 6 [ppm] = 1.16-1.19 (m, 3H), 1.33-1.75 (m, 13H), 1.96-2.00 (m, 1 H), 2.01-2.13 (m, 1 H), 2.14-2.33 (m, 2H), 2.42-2.52 (m, 2H), 5.17 (ddq, J=7.9, 6.8, 1.3, 1 H).

¹³C NMR (75 MHz, CDCI3) 6 [ppm] = 16.0/23.5 (CH₃), 17.00/17.01 (CH₃), 23.4/23.6 (CH₂), 25.4/25.5 (CH₂), 29.9 (CH₃), 31.6/39.5, 33.2/33.4 (CH₂), 39.3 (CH), 43.3/43.6 (CH₂), 68.38/68.43 (Cquat), 71.67/71.69 (CH_sp), 87.5/87.6 (Cquat), 124.0/124.7 (CH), 135.9/136.1 (Cquat), 182.9/183.0 (Cquat).

HRMS (El, after silylation) (C₂iH₄o0₃Si₂ ⁺): 396.2523; Calcd.: 396.2516.

Synthesis of 10-hydroxy-2, 6, 10-trimethyldodec-6, 11 -dienoic acid (l-A)

10-hydroxy-2,6, 10-trimethyldodec-6-en-11 -ynoic acid (I I l-A)

In a 150 mL steel autoclave, 10-hydroxy-2,6,10-trimethyldodec-5-en-11- ynoic acid (I I l-A) (5.93 g) was dissolved in ethyl acetate (85 mL). Lindlar catalyst (5% Pd/CaCOs with 3.5% Pb,700 mg) and 3,6-Dithia-1 ,8-octandiol (130 mg) were added. The autoclave was purged 3 times with nitrogen (pressurised to 5 barg and released) and 3 times with hydrogen (pressurised to 5 barg and released). The reaction mixture was heated to 25 °C, pressurised with 5 bar (0.5 MPa) H₂ and stirred for 2 h. After cooling the reaction mixture was filtered and the solvent was removed under reduced pressure to yield a crude product 10-hydroxy-2,6,10- trimethyldodec-6,11 -dienoic acid (l-A) (5.70g). Characterisation of 10-hydroxy-2,6, 10-trimethyldodec-6, 11 -dienoic acid (mixture of (E)- and (Z)-isomers):

¹H N MR (300 MHz, CDCI₃) 6 [ppm] = 1 .14-1 .22 (m, 3H), 1.25-1.31 (m, 3H), 1.32- 1.73 (m, 10H), 1.91-2.11 (m, 4H), 2.38-2.54 (m, 1 H), 5.06 (dd, J=10.7, 1.3, 1 H), 5.13 (tq, J=7.2, 1.3, 1 H), 5.21 (dd, J=17.3, 1.3, 1 H), 5.84-5.97 (m, 1 H).

¹³C NMR (75 MHz, CDCI3) 6 [ppm] = 16.0/23.5 (CH₃), 17.0/17.1 (CH₃), 22.6/22.8 (CH₂), 25.4/31.6 (CH₂), 28.0 (CH₃), 33.2/33.5 (CH₂), 39.3 (CH), 39.5 (CH₂), 42.2/42.5 (CH₂), 111.9 (CH₂), 124.7/125.3 (CH), 135.3 (Cquat), 145.1 (CH), 142.5 (Cquat).

FT-IR: v [cm^-1] = 690, 637, 842, 919, 995, 1162, 1206, 1290, 1376, 1413, 1458, 1705, 2932, 2971.

HRMS (El) after silylation (C₂iH42O3Si₂ ⁺): 398.2659; Calculated: 398.2673.

Synthesis of 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A)

10-hydroxy-2, 6, 10-trimethyldodec-6, 11 -dienoic acid (I -A) (3.25 g, 82 wt.%, 10.5 mmol) and 2-methoxyprop-1 -ene (6 g, 8 mL, 98 w%, 80 mmol) were added to a 100 mL stainless steel reactor. The reactor was closed and the solution was heated at 100 °C for 12 h. 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 as an orange oil (3.58 g, 58% combined yield of isomers by GC with internal standard). The crude product 2,6, 1 O-trimethyl-14- oxopentadeca-6,10-dienoic acid (IV-A) was purified by column chromatography on silica gel.

Characterisation of 2,6, 1 O-trimethyl-14-oxopentadeca-6, 10-dienoic acid):

¹H NMR (600 MHz, CDCI3) 6 [ppm] = 1.18 (ddd, J=7.0, 3.8, 1.6, 3 H), 1.35-1.47 (m, 3 H), 1.56-1.69 (m, 7 H), 1.94-2.10 (m, 6 H), 2.12-2.17 (m, 3 H), 2.21-2.30 (m, 2 H), 2.41-2.52 (m, 3 H), 5.04-5.15 (m, 2 H).

¹³C NMR (151 MHz, CDCI3) 6 [ppm] = 136.5, 136.4, 136.3, 136.3, 135.1 , 134.9,

134.8, 134.6, 125.1 , 125.1 , 124.4, 124.3, 123.3, 123.3, 122.6, 122.5, 77.2, 77.0, 76.8, 44.0, 43.8, 43.8, 39.9, 39.6, 39.4, 39.4, 39.3, 39.3, 39.3, 39.2, 39.2, 33.4,

33.3, 33.1 , 33.1 , 32.1 , 31.8, 31.5, 31.5, 30.0, 30.0, 29.9, 26.4, 26.4, 26.3, 25.6,

25.4, 25.4, 25.3, 23.4, 23.4, 23.4, 23.3, 22.5, 22.5, 22.3, 22.2, 16.9, 16.9, 16.9,

16.0, 16.0, 15.8, 15.8.

Synthesis of 2,6,10-trimethyl-14-oxopentadecanoic acid (Vl-A)

In a steel autoclave, 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A) (100 mg, 94.1 % purity, 0.32 mmol) was dissolved in EtOAc (1.7 mL). 5 mg Pd/C was added and the mixture was purged 3 times with argon (pressurised to 5 barg and released) and 3 times with hydrogen (pressurised to 5 barg and released). The reaction mixture was heated to 40 °C, pressurised with 5 bar (0.5 MPa) H2 and stirred for 3 h. After cooling to rt, it was filtered over a 0.45 pm membrane filter and the solvent was evaporated to give 95 mg (78.6% purity by q- NMR, 0.25 mmol, 78%) of the desired product 2,6,10-trimethyl-14- oxopentadecanoic acid (Vl-A) .

The product has been characterized as followed:

Characterisation of 2,6, 10-trimethyl-14-oxopentadecanoic acid):

¹H NMR (300 MHz, CDCI3) 6 [ppm] = 0.81-0.86 (m, 6H), 1.00-1.12 (m, 4H), 1.15- 1.19 (m, 3H), 1.19-1.45 (m, 11 H), 1.46-1.71 (m, 3H), 2.37-2.42 (m, 2H), 2.41- 2.49 (m, 1 H).

¹³C NMR (75 MHz, CDCI3) 6 [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 (El) after silylation (C2iH₄2O₃Si⁺): 370.2897; Calculated: 370.2903 Synthesis of 14-hydroxy-2,6,10 ,14-tetramethylhexadec-15-ynoic acid (lll-B)

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 (Vl-A) (33.21 mmol) at 15°C. The reaction was performed by addition of ethyne (9.4 bar (0.94 MPa), 1200 rpm) over 1 h. The solvent (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 HCI (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 concentrated under reduced pressure to give 14-hydroxy-2,6,10,14-tetramethylhexadec- 15-ynoic acid (lll-B), (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, CDCI₃) 6 [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, CDCI3) 6 [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 (l-B)

In a 50 mL glass insert for an autoclave, 14-hydroxy-2,6,10,14-tetra- methylhexadec-15-ynoic acid (lll-B) (5.0 g) was dissolved in toluene (30 mL). Lindlar catalyst (5% Pd/CaCOs with 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 mixture was purged 3 times with nitrogen (pressurised to 5 barg and released) and 3 times with 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 room temperature, it was filtered over a 0.45 pm membrane filter, rinsing with toluene, and the solvent was removed under reduce pressure. The crude product 14- hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (l-B) was purified by two rounds of column chromatography on silica gel to give 1.17 g (87% purity by q- NMR, 3.12 mmol,) 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, CDCI3) 5 [ppm] = 0.84 (d, J=6.4, 6 H), 0.98-1.56 (m, 25 H), 1.57-1.75 (m, 1 H), 2.37-2.55 (m, 1 H), 5.04 (dd, J=10.8, 1.3, 1 H), 5.20 (dd, J=17.3, 1.3, 1 H), 5.92 (dd, J=17.4, 10.8, 1 H).

¹³C NMR (75 MHz, CDCI3) 6 [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 (El, after silylation) (C₂₆H54O₃Si⁺): 470.3631 ; Calculated: 470.3612. i-2-yl)-2,6,10-

13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6, 10-trimethyltrideca- noic acid (VII) has been synthesized from 14-hydroxy-2,6,10,14-tetramethylhexa- dec-15-enoic acid (l-B) and is 2,3,6-trimethyl hydroquinone (Vlll-A) according to the procedure disclosed on page 2439 by Weichet J., Blaha 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, CDCI₃) 6 [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, 1 H), 2.60 (t, J=6.9, 2H).

¹³C NMR (75 MHz, CDCI3) 6 [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 (C_quat), 118.7 (C_quat), 121 .2 (C_quat), 122.7 (C_quat), 144.6 (Cquat), 145.7 (Cquat), 183.4 (Cquat).

HRMS (ESI) (C₂₉H₄8O4⁺): 460.3527; Calcd.: 460.3547.

Claims

1 . A process for the manufacture of an allylic alcohol the formula (I)

by the steps a) ethynylation of an unsaturated ketone of the formula (II)

followed by b) hydrogenation of the propargylic alcohol of the formula (III) formed in step a) using molecular hydrogen or a hydrogen donor or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to yield the compound of the formula (I); wherein n stands for a value of 0 to 3 and m stands for a value of 1 to 3 with the proviso that the sum of n and m is 1 to 3, and where the substructures in formula (I), (II) or (III), represented by s1 and s2, can be in any sequence; and 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 to the C=C double bond.

2. The process according to claim 1 , characterized in that step a) is performed in the absence of any organic solvent.

3. The process according to claim 1 or 2, characterized in that m=1 and n=1 .

4. An allylic alcohol of the formula (l-A)

wherein any wavy line represents independently from each other a carboncarbon bond which is either in the Z- or in the E-configuration with respect to the C=C double bond.

5. A propargylic alcohol of the formula (lll-A)

6. A process for the manufacture of the unsaturated ketone of the formula (IV’)

comprising the reaction step c) c) reacting an allylic alcohol of the formula (I’)

with a compound of the formula (Va) or (Vb)

in the absence of any strong acid, having a pka of less than 4, particularly of less than 2, preferably of less than 1 , measured in water at room temperature, or ammonium catalyst; wherein n stands for a value of 0 to 3, and m’ stands for 0 or m, wherein m stands for a value of 1 to 3, with the proviso that that the sum of n and m’ is 1 to 3 and where the substructures in formula (I’) or (IV’), represented by s1 and s2, can be in any sequence; and

R³ represents a methyl or an ethyl group;

R⁴ represents H or methyl or an ethyl group; R⁵ represents a linear or branched Ci -1 o-alkyl group, particularly a methyl or an ethyl group;

7. The process according to claim 6, characterized in that R³ represents a methyl group.

8. The process according to claim 6 or 7, characterized in that R⁴ represents H.

9. The process according to claim 6 or 7 or 8, characterized in that m’=m.

10. The process according to claim 6 characterized in that the compound of the formula (I’) is the compound of the formula (I) prepared by a process for the manufacture of an allylic alcohol of the formula (I) according to any one of the preceding claims 1 to 3.

11. A process according to claim 6, characterized in that that the compound of the formula (I’) is an allylic alcohol of the formula (l-A) according to claim 4.

12. An unsaturated ketone of the formula (IV-A)

13. A process for the manufacture of the saturated ketone of the formula (VI’)

wherein the ketone of formula (VI’) is obtained by hydrogenation of the compound of the unsaturated ketone of the formula (IV’) in the presence of molecular hydrogen, or a hydrogen donor or a transfer hydrogenation agent, preferably molecular hydrogen, and a transition metal catalyst

the transition metal is a transition metal of the groups 7, 8, 9 or 10, particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, more preferably Pd; and n stands for a value of 0 to 3, and m’ stands for 0 or m, wherein m stands for a value of 1 to 3, with the proviso that that the sum of n and m’ is 1 to 3 and where the substructures in formula (IV’) or (VI’), represented by s1 and s2, can be in any sequence; and 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 to the C=C double bond; characterized in that the compound of the formula (IV’) is prepared by a process for the manufacture of the ketone of the formula (IV’) according to any of the preceding claims 6 to 8.

14. The process according to claim 13, wherein the compound of formula (I’) has been manufactured according to any one of claims 1 to 3.

15. A process according to claim 13, characterized in that R³ represents a methyl group and R⁴ represents H group and that the saturated ketone of the formula (VI’) is the saturated ketone of the formula (Vl-A)

16. A process for the manufacture of the allylic alcohol of the formula (l-B) comprising the steps

by the steps c) ethynylation of the saturated ketone of the formula (Vl-A)

to yield a propargylic alcohol of the formula ( 11 l-B)

followed by d) hydrogenation of the propargylic alcohol of the formula ( 11 l-B) formed in step a) using molecular hydrogen or a hydrogen donor or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to yield the allylic alcohol of the formula (l-B); characterized in that the saturated ketone of the formula (Vl-A) is prepared according to a process according to claim 15.

17. A process for the manufacture of the compound of the formula (VII) comprising the steps i) preparing an allylic alcohol of the formula (l-B)

according to a process for the manufacture of an allylic alcohol of the formula (l-B) according to claim 16; ii) reacting the compound of the formula (l-B) with the compound of the formula (VIII) to yield a compound of the formula (VII)

R²⁰ represents hydrogen or R' which is a phenol protecting group; and R¹⁰ and R¹¹ and R¹² represent independently from each other hydrogen or a methyl group; and R²¹ represents hydrogen or R' which is a phenol protecting group.