The present invention is directed to a process for the manufacture of 6, 10- dimethylundecan-2-one comprising the step of hydrogenating (5Z)-neryl- acetone (=(Z)-6, 10-dimethylundeca-5,9-dien-2-one) with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon-oxygen double bonds. Preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof. More preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum and mixtures thereof. Even more preferably the catalyst is a metal selected from the group consisting of palladium, platinum and mixtures thereof. Most preferably the catalyst is palladium.

Surprisingly the inventors of the present invention discovered that when (5Z)-nerylacetone is used as starting material for the synthesis of 6, 10- dimethylundecan-2-one, the hydrogenation reaction is much faster than in the case, where a mixture of (5Z)-nerylacetone (= (Z)-6, 10-dimethylundeca- 5,9-dien-2-one) and (5E)-geranylacetone (=(E)-6, 10-dimethylundeca-5,9- dien-2-one) is used. Therefore, it is advantageous, especially for an industrial process, where hundreds of tons are produced, to use as starting material for obtaining 6, 10-dimethylundecan-2-one cis/trans-isomeric pure (5Z)-nerylacetone, because the time savings have an immense influence on the overall production costs.

The 6, 10-dimethylundecan-2-one obtained according to the process of the present invention may be used as starting material for isophytol and a- tocopherol (acetate) via 3,7, 1 1 -trimethyl-dodec-1 -en-3-ol ("tetrahydro- nerolidol"; THNL), 6, 10, 14-trimethylpentadec-5-en-2-one ("(5E/5Z)-5,6- dehydro-C18-ketone") and 6, 10, 14-pentadecane-2-one or alternatively via 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol, 6, 10, 14-trimethylpentadec-4,5-dien-2-one ("C18-allene-ketone") and 6, 10, 14-pentadecane-2-one ("C18-ketone"). Thus, the present invention is also directed to such processes which comprise the step of hydrogenating (5Z)-nerylacetone according to the process of the present invention.

Detailed description

There was a need to further optimize the synthesis of isophytol, an important starting material for a-tocopherol and its acetate. 6, 10- dimethylundecan-2-one is the starting material for isophytol. Thus, an improvement in the synthesis of 6, 10-dimethylundecan-2-one leads also to an improvement in the synthesis of isophytol.

This need is fulfilled by the present invention, which is directed to a process for the manufacture of 6, 10-dimethylundecan-2-one comprising the step of hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon-oxygen double bonds (see Fig. 1 ). This process corresponds to the first step (step a)) in the process for the manufacture of 3,7, 1 1 -trimethyl-dodec-1 -en-3-ol ("tetrahydronerolidol"; THNL), 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol, 6, 10, 14-trimethylpentadec-4,5- dien-2-one ("C18-allene-ketone"), 6, 10, 14-trimethylpentadec-5-en-2-one, 6, 10, 14-pentadecane-2-one ("C18-ketone"), isophytol and a-tocopherol or its acetate. Starting material

The (5Z)-nerylacetone used as starting material may come from natural sources or any other source or obtained by fermentation or may be synthesized synthetically and, if needed, separated from (5E)- geranylacetone by any method known to the person skilled in the art. Nerylacetone may for example be synthesized starting from linalool (see Fig. 9) in a Carroll reaction as described in CN-A 102 1 1 5 437, WO 2010/046199, DE 198 40 746 and JP-A 2002 121 165 or by reaction with isopropenyl alkyl ethers as described in DE 196 49 564 or by reaction with the dimethylacetal of acetone as described by P. Baeckstroem and L. Li in Tetrahedron 1991 , 47(32), 6521 -6532. An alternative synthesis is disclosed by Sato, Kikumasa; Miyamoto, Osamu; Inoue, Seiichi; Kobayashi, Toru; and Furusawa, Fumio in Chemistry Letters, 1981 , 171 1 -14 ("A stereoselective formation of (Z)-2- methyl-2-alkenol by the Wittig reaction: its application to a synthesis of nerylacetone and (Z,Z)-farnesylacetone").

It is preferred that the hydrogenation of (5Z)-nerylacetone is performed in the presence of (5E)-geranylacetone of below 10 mol-%, preferably below 5 mol-%, more preferably below 2 mol-%, based on the total amount of (5E)- geranylacetone and (5Z)-nerylacetone. Thus, a mixture of (5E)- geranylacetone and (5Z)-nerylacetone, where the amount of (5E)- geranylacetone is up to 10 mol-%, based on the total amount of the mixture, may also be used successfully.

More preferably, however, the hydrogenation of (5Z)-nerylacetone is performed using (5Z)-nerylacetone as cis/trans isomeric pure (5Z)- nerylacetone.

The term ^" cis/trans isomeric pure ^" , as used in this document, refers to the purity in respect to the amount of the isomers having different cis/trans (or E/Z) configuration at the carbon-carbon double bond as sole difference. A compound considered as ^" cis/trans isomeric pure ^" has more than 99-mol % of the compound with the indicated configuration.

In other words, ^" cis/trans isomeric pure (5Z)-nerylacetone ^" is a mixture of as more than 99 mol-% (5Z)-nerylacetone and less than 1 mol-% of (5E)- geranylacetone.

Most preferred, the hydrogenation of using (5Z)-nerylacetone is performed in the absence of (5E)-geranylacetone. Catalyst

Preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof. More preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum and mixtures thereof.

Even more preferably the catalyst is a metal selected from the group consisting of palladium, platinum and mixtures thereof. Most preferably the catalyst is palladium.

Of the catalysts described above, those catalysts are even more preferred that comprise a support/carrier being selected from the group consisting of carbon, graphite, inorganic oxides, inorganic carbonates, inorganic sulfates, as well as mixtures thereof where the active component (i.e. the metal) is deposited on. Preferred support/carrier materials are carbon, silicon dioxide, aluminum oxide and calcium carbonate, as well as mixtures thereof. An example for such mixtures are silica-alumina-mixtures.

If the active metal catalyst is used on a support/carrier material, the active metal catalyst content 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 mass of active metal catalyst and support.

The amount of the active component of the catalyst (being preferably a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof) is preferably in the range of from 0.0001 to 1 weight%, more preferably in the range of from 0.001 to 0.5 weight%, most preferably in the range of from 0.01 to 0.1 weight%, based on the weight of the starting material, the (5Z)-nerylacetone. Reaction conditions

The hydrogenation reaction is preferably carried out at a temperature in the range of from 10 to 150° C, more preferably at a temperature in the range of from 20 to 100° C, most preferably at a temperature in the range of from 50 to 90 ^° C.

The hydrogenation reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar hydrogen absolute, more preferably at a hydrogen pressure in the range of from 2 to 10 bar hydrogen absolute, even more preferably at a hydrogen pressure in the range of from 2 to 6 bar hydrogen absolute, further more preferably at a hydrogen pressure in the range of from 2.5 to 4 bar hydrogen absolute most preferably at a hydrogen pressure of around 3 bar hydrogen absolute.

Solvent

The hydrogenation reaction can be carried out without solvent or in the presence of an organic solvent. Preferably the reaction is carried out in an organic solvent. The organic solvent is preferably selected from the group consisting of hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, amides, nitriles and ketones and mixtures thereof. More preferred are C ₄ -Cio

aliphatic hydrocarbons, C ₆ -Cio aromatic hydrocarbons, C ₆ -Cio aromatic hydrocarbons substituted with one or more Ci -C ₄ linear alkyl groups or C ₃ -C ₄ branched alkyl groups or halogens, Ci -C ₄ linear alcohols or C ₃ -C ₄ branched alcohols, acyclic and cyclic C ₄ -Cio ethers, C ₃ -Cio esters, C ₃ -Cio ketones and mixtures thereof.

Especially preferred organic solvents are selected from the group consisting of hexane, heptane, toluene, methanol, ethanol, n-propanol, 2-propanol, n- butanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, acetone, and mixtures thereof. The most preferred organic solvents are heptane and ethanol. The amount of solvent is preferably in the range of from 0 to 100 volumes (0 = solvent free), more preferably in the range of from 0.1 to 10 volumes, most preferably in the range of from 1 to 5 volumes, based on the volume of the starting material, the (5Z)-nerylacetone.

Process for the manufacture of 3,7, 1 1 -trimethyl-dodec-1 -vn-3-ol

The 6, 10-dimethylundecan-2-one obtained according to the process of the present invention is ethynylated according to any process known to the person skilled in the art to yield 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol (see Fig.

6). The ethynylation may either be performed with acetylene, ammonia and a base, for example potassium hydroxide, or with an ethynyl Grignard.

Thus, the present invention is directed to a process for the manufacture of 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol comprising the following steps: a) hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst to obtain 6, 10-dimethylundecan-2-one according to the process of the present invention;

b1 ) ethynylating 6, 10-dimethylundecan-2-one obtained in step a) to obtain 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol.

Process for the manufacture of 3,7, 1 1 -trimethyl-dodec-1 -en-3-ol

("tetrahydronerolidol"; THNL)

The 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol is then hydrogenated in presence of a Lindlar catalyst to THNL. Alternatively 6, 10-dimethylundecan-2-one may be reacted with vinyl Grignard according to a process known by the person skilled in the art to THNL (see Fig. 2). Thus, the present invention is directed to a process for the manufacture of 3,7, 1 1 -trimethyl-dodec-1 -en-3-ol comprising the following steps: a) hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst to obtain 6,10-dimethylundecan-2-one according to the process of the present invention;

b1) ethynylating 6,10-dimethylundecan-2-one to obtain 3,7,11- trimethyl-dodec-1 -yn-3-ol;

c1) hydrogenating 3,7,11-trimethyl-dodec-1-yn-3-ol to obtain 3,7,11- trimethyl-dodec-1 -en-3-ol.

A further object of the present invention is also a process for the

manufacture of 3,7,11-trimethyl-dodec-1-en-3-ol comprising the following steps:

a) hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon-oxygen double bonds, to obtain 6,10-dimethylundecan-2-one; b2) vinylating 6,10-dimethylundecan-2-one by addition of a vinyl

Grignard reagent to yield 3,7,11-trimethyl-dodec-1-en-3-ol.

That means that in the process for the manufacture of 3,7,11-trimethyl- dodec-1-en-3-ol a step b2) can be performed instead of performing step b1) and c1 ) to obtain 3,7, 11 -trimethyl-dodec-1 -en-3-ol.

Process for the manufacture of a mixture of (5E)-6, 10,14- trimethylpentadec-5-en-2-one and (5Z)-6,10,14-trimethylpentadec-5-en-2- one

Such a mixture of (5E)-6,10,14-trimethylpentadec-5-en-2-one and (5Z)-

6,10,14-trimethylpentadec-5-en-2-one can be obtained by C3 elongation of tetrahydronerolidol ("THNL") (see Fig.3). An example is the reaction of THNL with isopropenyl methyl ether or with isopropenyl ethyl ether in the presence of a catalyst to the mixture of (5E)-6,10,14-trimethylpentadec-5- en-2-one and (5Z)-6,10,14-trimethylpentadec-5-en-2-one. As catalyst either an acid or an ammonium salt can be used. The process wherein the catalyst is an acid, preferably wherein the catalyst is selected from the group consisting of phosphoric acid, sulfuric acid, p- toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, oxalic acid and mixtures thereof, is further described in WO 2009/019132 whose content is hereby incorporated by reference.

The process wherein the catalyst is an ammonium salt, preferably wherein the catalyst is selected from the group consisting of ammonium bromide, ammonium chloride or di-ammonium phosphate, is further described in WO 2010/046199 whose content is hereby incorporated by reference.

Alternatively the C3 elongation of THNL may also be carried out according to the process as described in JP-A 2002-121 165.

Furthermore the C3 elongation of THNL may also be carried out with one of the following reagents according to processes known to the person skilled in the art.

Process for the manufacture of 6, 10, 14-trimethylpentadec-4,5-dien-2-one 6, 10, 14-trimethylpentadec-4,5-dien-2-one can be obtained by C3 elongation of 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol as obtained according to the process of the present invention. The C3 elongation is preferably carried out by reacting 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol with isopropenyl methyl ether or with isopropenyl ethyl ether in the presence of a catalyst, to obtain 6, 10, 14- trimethylpentadec-4,5-dien-2-one (see Fig. 7). As catalyst either an acid or an ammonium salt can be used. The process wherein the catalyst is an acid, preferably wherein the catalyst is selected from the group consisting of phosphoric acid, sulfuric acid, p- toluenesulfonic acid, methanesulfonic acid and mixtures thereof, is further described in WO 2008/092655 whose content is hereby incorporated by reference.

Process for the manufacture of 6, 10, 14-t methylpentadecan-2-one

The present invention is also directed to a process for the manufacture of

6, 10, 1 -trimethylpentadecan-2-one comprising the following steps:

a) hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst to obtain 6, 10-dimethylundecan-2-one according to the process of the present invention;

b1 ) ethynylating 6, 10-dimethylundecan-2-one obtained in step a) to obtain 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol (see Fig. 6);

c1 ) hydrogenating 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol obtained in step b1 ) to obtain 3,7, 1 1 -trimethyl-dodec-1 -en-3-ol (tetrahydronerolidol);

C3 elonging the thus obtained 3,7, 1 1 -trimethyl-dodec-1 -en-3-ol, preferably by reacting it with isopropenyl methyl ether or with isopropenyl ethyl ether in the presence of a catalyst, to obtain a mixture of (5E)-6, 10, 14-trimethylpentadec-5-en-2-one and (5Z)-

6, 10, 1 -trimethylpentadec-5-en-2-one; hydrogenating the thus obtained mixture of (5E)-6, 10, 14- trimethylpentadec-5-en-2-one and (5Z)-6, 10, 14-trimethylpentadec-5- en-2-one with hydrogen in the presence of a catalyst to obtain 6, 10, 14- trimethylpentadecan-2-one.

Instead of steps b1 ) and c1 ) the following step can also be performed:

b2) vinylating 6, 10-dimethylundecan-2-one obtained in step a) by addition of a vinyl Grignard reagent to yield 3,7, 1 1 -trimethyl-dodec-1 -en-3-ol (see Fig. 2). The present invention is also directed to an alternative process for the manufacture of 6, 10, 14-trimethylpentadecan-2-one comprising the followin steps:

a) hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst to obtain 6, 10-dimethylundecan-2-one according to the process of the present invention;

b1 ) ethynylating 6, 10-dimethylundecan-2-one obtained in step a) to obtain 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol; C3 elonging 3,7, 1 1 -trimethyl-dodec-1 -yn-3-ol as obtained in step b1 ), preferably by reacting it with isopropenyl methyl ether or with isopropenyl ethyl ether in the presence of a catalyst, to obtain 6, 10, 14- trimethylpentadec-4,5-dien-2-one (see Fig. 7); hydrogenating the thus obtained 6, 10, 14-trimethylpentadec-4,5-dien-2- one with hydrogen in the presence of a catalyst to obtain 6, 10, 14- trimethylpentadecan-2-one (see Fig. 8).

Process for the manufacture of isophytol, q-tocopherol and its acetate

Since 6, 10, 14-trimethylpentadecan-2-one ("C18-ketone") is an important starting material for isophytol (see Fig. 5), and thus for a-tocopherol and its acetate, the present invention is also directed to a process for the

manufacture of isophytol and for the manufacture of α-tocopherol and its acetate, respectively, comprising the process according to the present invention.

Thus, the present invention is directed to a process for the manufacture of isophytol comprising the following steps:

a) hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon-oxygen double bonds, to obtain 6,10-dimethylundecan-2-one according to the process of the present invention as described in detail above;

b1) ethynylating 6,10-dimethylundecan-2-one to obtain 3,7,11-trimethyl- dodec-1-yn-3-ol;

c1) hydrogenating 3,7,11-trimethyl-dodec-1-yn-3-ol with hydrogen in the presence of a Lindlar catalyst to obtain 3,7,11-trimethyl-dodec-1-en-3-ol; d) C3 elonging 3,7,11-trimethyl-dodec-1-en-3-ol, preferably with

isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E)-6,10,14-trimethylpentadec-5-en-2-one and (5Z)-6,10,14-trimethylpentadec-5-en-2-one;

e) hydrogenating the mixture of (5E)-6,10,14-trimethylpentadec-5-en-2-one and (5Z)-6,10,14-trimethylpentadec-5-en-2-one with hydrogen in the presence of a catalyst to obtain 6,10,14-trimethylpentadecan-2-one;

f1) ethynylating 6,10,14-trimethylpentadecan-2-one to obtain 3,7,11,15- tetramethylhexadec-1 -yn-3-ol;

g1) hydrogenating 3,7,11,15-tetramethylhexadec-1-yn-3-ol with hydrogen in the presence of a Lindlar catalyst to obtain isophytol.

The steps b1 ), c1 ), d), e), f 1 ) and g1 ) may be carried out according to methods known to the person skilled in the art. The ethynylation (steps b1 ) and f1)) e.g. may either be performed with acetylene, ammonia and potassium hydroxide or with ethynyl Grignard. The following hydrogenation of the CC triple bond to a C=C double bond is then carried out with a Lindlar catalyst (steps c1 ) and g1 )).

Instead of steps b1 ) and c1 ) a step b-c2) may be performed as follows:

vinylating 6,10-dimethylundecan-2-one by addition of a vinyl Grignard reagent to yield 3,7,11-trimethyl-dodec-1-en-3-ol. Instead of steps f 1 ) and g1 ) a step f-g2) may be performed as follows:

Vinylating 6,10,14-trimethylpentadecan-2-one to obtain isophytol. Alternatively isophytol may be manufactured by a process comprising the steps as follows which is also an embodiment of the present invention:

a) hydrogenating (5Z)-nerylacetone with hydrogen in the presence of a catalyst to obtain 6, 10-dimethylundecan-2-one according to the process of the present invention;

b1 ) ethynylating 6, 10-dimethylundecan-2-one obtained in step a) to obtain 3,7, 11 -trimethyl-dodec-1 -yn-3-ol;

d2) C3 elonging 3,7, 11 -trimethyl-dodec-1 -yn-3-ol obtained in step b1 ), preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain 6, 10,14- trimethylpentadec-4,5-dien-2-one;

e2) hydrogenating 6,10, 1 -trimethylpentadec-4,5-dien-2-one obtained in step d2) with hydrogen in the presence of a catalyst to obtain 6, 10, 14-trimethylpentadecan-2-one;

f1 ) ethynylating 6,10, 14-trimethylpentadecan-2-one obtained in step e2) to obtain 3,7,11 , 15-tetramethylhexadec-1 -yn-3-ol;

g1 ) hydrogenating 3,7, 11 , 15-tetramethylhexadec-1 -yn-3-ol obtained in step f 1 ) with hydrogen in the presence of a Lindlar catalyst to obtain isophytol.

A further object of the present invention is a process for the manufacture of a-tocopherol and its acetate, respectively, comprising the following steps: i) manufacturing isophytol as described above;

ii) coupling isophytol with 2,3,5-trimethylhydroquinone or 2,3,5- trimethylhydroquinone acetate to obtain a-tocopherol or its acetate.

Step ii) may also be performed according to any method known in the prior art. The invention is now further illustrated in the following non-limiting examples.

Examples

Standard Protocol for Hydrogenation Reactions

A mixture of the substrate nerylacetone/geranylacetone (20 g) (either cis/trans isomeric pure (5Z)-nerylacetone or a mixture of (5E)-geranyl- acetone and (5Z)-nerylacetone) and solvent (20 g) is added to a 125 ml steel autoclave. The catalyst is added and the reactor is sealed. The mixture is purged three times with nitrogen (pressurise to 5 bar, then release) and three times with hydrogen (pressurise to 5 bar, then release). The reactor is heated to the desired temperature and then pressurised with hydrogen to the desired pressure. Stirring is started at 1000 rpm and the hydrogen uptake is recorded. After a total experiment time of 18 hours the reaction mixture is cooled to room temperature, the pressure is released and a sample taken for quantitative GC analysis.

Hydrogenation Results

The examples given below show that the hydrogenation of (5Z)-nerylacetone alone proceeds faster than the hydrogenation of a mixture of (5E)-geranyl- acetone and (5Z)-nerylacetone. The sample of cis/trans isomeric pure (5Z)- nerylacetone used had less than 1 % of (5E)-geranylacetone. The following catalysts are used:

- a 5% Pd/Al ₂ 0 ₃ egg-shell catalyst with a BET surface area of 93 m ² /g and a pore volume of 0.3 ml/g as e.g. commercially available from Evonik under the tradename "5% Pd/Al ₂ 0 ₃ E 213 R/D";

- a 5% Pd/C as e.g. commercially available from Evonik under the tradename "5% Pd/C E 101 O/D" Table 1 : Catalyst used = 5% Palladium on Carbon as commercially available from Evonik

^* cis/trans isomeric pure (5Z)-nerylacetone

Table 2: Catalyst used = 5% Palladium on Alumina as commercially available from Evonik

*cis/trans isomeric pure (5Z)-nerylacetone